NP_004295.2:p.Asp1529Glu in Exon 29 of ALK (NM_004304.4:c.4587C>G) Pathogenic

This is a Missense Variant located in the ALK gene.

It has been associated with Neuroblastoma susceptibility to 3.

Molecular basis is known for 613014 because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (105590) on chromosome 2p23.

For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

Molecular basis is known for 613014 because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (105590) on chromosome 2p23.

For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

NP_004295.2:p.Val476Ala in Exon 7 of ALK (NM_004304.4:c.1427T>C) Pathogenic

This is a Missense Variant located in the ALK gene.

It has been associated with Neuroblastoma susceptibility to 3.

Molecular basis is known for 613014 because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (105590) on chromosome 2p23.

For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

Molecular basis is known for 613014 because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (105590) on chromosome 2p23.

For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

NP_066124.1:p.Arg360Trp in Exon 6 of RET (NM_020975.4:c.1078C>T) Pathogenic

This is a Missense Variant located in the RET gene.

The RET protooncogene is one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation. The RET gene was defined as an oncogene by a classical transfection assay. RET can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement (Grieco et al., 1990). Mutations in the RET gene are associated with multiple endocrine neoplasia, type IIA (MEN2A; 171400), multiple endocrine neoplasia, type IIB (MEN2B; 162300), Hirschsprung disease (HSCR; aganglionic megacolon; 142623), and medullary thyroid carcinoma (MTC; 155240).

{121:Plaza-Menacho et al. (2006)} reviewed the genetics and molecular mechanisms underlying the different inherited neural crest-related disorders involving RET dysfunction.

This gene has been observed to exhibit Autosomal dominant and Autosomal recessive inheritance pattern.

It has been associated with Central hypoventilation syndrome congenital, Medullary thyroid carcinoma, Multiple endocrine neoplasia IIA, Multiple endocrine neoplasia IIB, Pheochromocytoma, Renal agenesis, and Hirschsprung disease susceptibility to 1.

The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur.

Genetic Heterogeneity of Hirschsprung Disease

Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32.

HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880).

Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases (Amiel et al., 2008). HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases.

Molecular basis is known for 142623 because of evidence that susceptibility to Hirschsprung disease-1 (HSCR1) is associated with variation in the RET gene (164761) on chromosome 10q11.

Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996).

For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (131100).

Molecular basis is known for 162300 because of evidence that multiple endocrine neoplasia type IIB (MEN2B) is caused by heterozygous mutation in the RET gene (164761) on chromosome 10q11. Most patients (95%) carry a specific M918T mutation ({164761.0013}) in exon 16 of the RET gene.

Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (162300), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by Lore et al., 2001).

For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (131100).

Molecular basis is known for 171400 because multiple endocrine neoplasia type IIA (MEN2A) is caused by heterozygous mutation in the RET oncogene (164761) on chromosome 10q11.

The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur.

Genetic Heterogeneity of Hirschsprung Disease

Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32.

HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880).

Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases (Amiel et al., 2008). HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases.

Molecular basis is known for 142623 because of evidence that susceptibility to Hirschsprung disease-1 (HSCR1) is associated with variation in the RET gene (164761) on chromosome 10q11.

Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996).

For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (131100).

Molecular basis is known for 162300 because of evidence that multiple endocrine neoplasia type IIB (MEN2B) is caused by heterozygous mutation in the RET gene (164761) on chromosome 10q11. Most patients (95%) carry a specific M918T mutation ({164761.0013}) in exon 16 of the RET gene.

Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (162300), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by Lore et al., 2001).

For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (131100).

Molecular basis is known for 171400 because multiple endocrine neoplasia type IIA (MEN2A) is caused by heterozygous mutation in the RET oncogene (164761) on chromosome 10q11.

NP_000029.2:p.Val1822Asp in Exon 16 of APC (NM_000038.5:c.5465T>A)

This is a Missense Variant located in the APC gene.

The APC gene encodes a multidomain protein that plays a major role in tumor suppression by antagonizing the WNT (see WNT1; 164820) signaling pathway. Inappropriate activation of this pathway through loss of APC function contributes to cancer progression, as in familial adenomatous polyposis (FAP; 175100). APC also has a role in cell migration, adhesion, chromosome segregation, spindle assembly, apoptosis, and neuronal differentiation (Hanson and Miller, 2005).

The APC protein is an integral part of the beta-catenin (CTNNB1; 116806) signaling pathway.

This gene has been observed to exhibit Autosomal dominant inheritance pattern.

It has been associated with Adenoma periampullary somatic, Adenomatous polyposis coli, Brain tumor-polyposis syndrome 2, Colorectal cancer somatic, Desmoid disease hereditary, Gardner syndrome, Gastric cancer somatic, and Hepatoblastoma somatic.

Hereditary desmoid disease usually presents as an extraintestinal manifestation of familial adenomatous polyposis (FAP; 175100), also known as Gardner syndrome, which is an autosomal dominant disorder caused by germline mutation in the APC gene. The desmoid tumors are usually intraabdominal and, although benign, can be locally aggressive and result in significant morbidity. Desmoid tumors can also arise sporadically (Couture et al., 2000).

Molecular basis is known for 135290 because hereditary desmoid disease has been found to be caused, at least in some cases, by mutation in the APC gene (611731) on chromosome 5q22.2.

A somatic mutation in the beta-catenin gene (CTNNB1; 116806) has been observed in a desmoid tumor derived from a patient with sporadic disease.

Hereditary desmoid disease usually presents as an extraintestinal manifestation of familial adenomatous polyposis (FAP; 175100), also known as Gardner syndrome, which is an autosomal dominant disorder caused by germline mutation in the APC gene. The desmoid tumors are usually intraabdominal and, although benign, can be locally aggressive and result in significant morbidity. Desmoid tumors can also arise sporadically (Couture et al., 2000).

Molecular basis is known for 135290 because hereditary desmoid disease has been found to be caused, at least in some cases, by mutation in the APC gene (611731) on chromosome 5q22.2.

A somatic mutation in the beta-catenin gene (CTNNB1; 116806) has been observed in a desmoid tumor derived from a patient with sporadic disease.

NP_000255.2:p.Pro1315Leu in Exon 23 of PTCH1 (NM_000264.3:c.3944C>T)

This is a Missense Variant located in the PTCH1 gene.

The Drosophila 'Patched' (ptc) gene encodes a transmembrane protein that represses transcription in specific cells of genes encoding members of the TGF-beta (see 190180) and Wnt (164820) families of signaling proteins. Vertebrate homologs of ptc have been identified in mice, chickens, and zebrafish.

This gene has been observed to exhibit Autosomal dominant inheritance pattern.

It has been associated with Basal cell carcinoma somatic, Basal cell nevus syndrome, and Holoprosencephaly-7.

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002).

Molecular basis is known for 610828 because of evidence that holoprosencephaly-7 (HPE7) is caused by heterozygous mutation in the PTCH1 gene (601309) on chromosome 9q22.

For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100).

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002).

Molecular basis is known for 610828 because of evidence that holoprosencephaly-7 (HPE7) is caused by heterozygous mutation in the PTCH1 gene (601309) on chromosome 9q22.

For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100).

5 Prime UTR Variant in PTCH1 (NM_001083602.1:c.-222G>A)

This is a 5 Prime UTR Variant located in the PTCH1 gene.

The Drosophila 'Patched' (ptc) gene encodes a transmembrane protein that represses transcription in specific cells of genes encoding members of the TGF-beta (see 190180) and Wnt (164820) families of signaling proteins. Vertebrate homologs of ptc have been identified in mice, chickens, and zebrafish.

This gene has been observed to exhibit Autosomal dominant inheritance pattern.

It has been associated with Basal cell carcinoma somatic, Basal cell nevus syndrome, and Holoprosencephaly-7.

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002).

Molecular basis is known for 610828 because of evidence that holoprosencephaly-7 (HPE7) is caused by heterozygous mutation in the PTCH1 gene (601309) on chromosome 9q22.

For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100).

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002).

Molecular basis is known for 610828 because of evidence that holoprosencephaly-7 (HPE7) is caused by heterozygous mutation in the PTCH1 gene (601309) on chromosome 9q22.

For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100).

NP_000235.2:p.Thr546Ala in Exon 10 of MEN1 (NM_000244.3:c.1636A>G)

This is a Missense Variant located in the MEN1 gene.

The MEN1 gene encodes menin, a nuclear scaffold protein that regulates gene transcription by coordinating chromatin remodeling. Menin interacts with several transcription factors, including JUND (165162), NFKB (164011), and SMAD3 (603109). MEN1 is considered to act as a tumor suppressor gene (summary by Canaff et al., 2012).

This gene has been observed to exhibit Autosomal dominant inheritance pattern.

It has been associated with Adrenal adenoma somatic, Angiofibroma somatic, Carcinoid tumor of lung, Lipoma somatic, Multiple endocrine neoplasia 1, and Parathyroid adenoma somatic.

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by Chandrasekharappa et al., 1997).

Genetic Heterogeneity of Multiple Endocrine Neoplasia

Other forms of multiple endocrine neoplasia include MEN2A (171400) and MEN2B (162300), both of which are caused by mutation in the RET gene (164761), and MEN4 (610755), which is caused by mutation in the CDKN1B gene (600778).

Molecular basis is known for 131100 because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (613733) on chromosome 11q13.

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by Chandrasekharappa et al., 1997).

Genetic Heterogeneity of Multiple Endocrine Neoplasia

Other forms of multiple endocrine neoplasia include MEN2A (171400) and MEN2B (162300), both of which are caused by mutation in the RET gene (164761), and MEN4 (610755), which is caused by mutation in the CDKN1B gene (600778).

Molecular basis is known for 131100 because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (613733) on chromosome 11q13.

NP_000536.5:p.Ile27Leu in Exon 1 of HNF1A (NM_000545.5:c.79A>C)

This is a Missense Variant located in the HNF1A gene.

Chiu et al. (2000) examined the relationship between the ile27-to-leu (I27L) polymorphism of HNF1-alpha and insulin sensitivity (see 125853) and beta-cell function assessed by a hyperglycemic clamp. This study included 52 healthy glucose-tolerant and normotensive subjects (age, 19 to 40 years; body mass index, 17.58-35.61 kg/m2; waist/hip ratio, 0.65-1.03). Chiu et al. (2000) identified 19 LL subjects, 24 IL subjects, and 9 II subjects. The LL group had the highest postchallenge insulin levels at 30 and 90 min (P = 0.038 and P = 0.015, respectively) and also the highest insulin area under curve (P = 0.009) among the 3 genotypes. The LL group was more insulin resistant than the IL and II groups (P = 0.042 for insulin sensitivity index). After adjusting for age, gender, obesity, and ethnicity, the I27L polymorphism was an independent determinant of the insulin sensitivity index (P = 0.001). However, it had no impact on either the first or second phase insulin response. The authors concluded that the I27L polymorphism is associated with insulin resistance, but not beta-cell function. The mechanism of this association is unclear, but HNF1-alpha may play a role in regulating hepatic glucose metabolism.

Babaya et al. (2003) studied the relationship of the HNF1A gene polymorphism I27L with lipid parameters, in particular with serum HDL cholesterol level, in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the 3 genotypes, the serum HDL cholesterol level was significantly associated with the genotype (P less than 0.01). Subjects with the II genotype had low serum HDL cholesterol levels, and those with the LL genotype had high serum HDL cholesterol levels. The authors concluded that the HNF1A gene locus is associated with serum HDL cholesterol level and suggested that the I27 allele is a risk marker for atherosclerosis.

This gene has been observed to exhibit Autosomal dominant and Autosomal recessive inheritance pattern.

It has been associated with Diabetes mellitus insulin-dependent 20, Hepatic adenoma somatic, MODY type III, Renal cell carcinoma, Diabetes mellitus insulin-dependent, and Diabetes mellitus noninsulin-dependent 2.

Molecular basis is known for 142330 because familial hepatic adenomas can occur through biallelic inactivation of the transcription factor-1 gene (TCF1, HNF1A; 142410) on chromosome 12q24. Hepatic adenomas also occur in high frequency with type I glycogen storage disease (232200).

Molecular basis is known for 600496 because of evidence that maturity-onset diabetes of the young type 3 (MODY3) is caused by mutation in the hepatocyte nuclear factor-1-alpha gene (142410), which maps to chromosome 12q24.2.

MODY is a form of familial noninsulin-dependent diabetes mellitus (NIDDM; 125853) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance. For general information on MODY and on genetic heterogeneity in this disorder, see 606391.

In their review of MODY, Fajans et al. (2001) stated that, not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations in the HNF4A gene (MODY1) and MODY due to mutations in the HNF1A (MODY3) are very similar since HNF4-alpha regulates the expression of HNF1-alpha. Patients with mutations in these genes may present with a mild form of diabetes. Despite similarly mild elevations in fasting plasma glucose concentrations, patients with mutations in HNF4A or HNF1A have significantly higher plasma glucose concentrations 2 hours after glucose administration than do persons with glucokinase mutations. The hyperglycemia in patients with MODY1 and MODY3 tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in may of these patients (30 to 40% require insulin). These forms of MODY are associated with a progressive decrease in insulin secretion. In most populations, mutations in the HNF1A gene are the most common cause of MODY. Patients with MODY1 or MODY3 may have the full spectrum of complications of diabetes. Microvascular complications, particularly those involving the retina or kidneys, are as common in these patients as in patients with type I or type II diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are probably determined by the degree of glycemic control. Patients with MODY1 lose the glucose priming effect of mild hyperglycemia on insulin secretion. Both prediabetic and diabetic persons with mutations in the HNF4A gene secrete decreased amounts of insulin in response to glucose and in response to arginine and also have an impairment of glucagon secretion in response to arginine. Furthermore, a defect in the hypoglycemia-induced secretion of pancreatic polypeptide has been found in prediabetic and diabetic persons who have mutations in the gene for HNF4A. These findings suggested that a deficiency of HNF4A resulting from mutations in this gene may affect the function of the beta, alpha, and pancreatic polypeptide cells within pancreatic islets. Patients with mutations in HNF1A have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria. A deficiency of HNF4A affects triglyceride and apolipoprotein biosynthesis and is associated with a 50% reduction in serum triglyceride concentrations and a 25% reduction in serum concentrations of apolipoproteins AII and CIII and Lp(a).

Fajans et al. (2001) reported that mutations in the HNF1A gene have been identified in all racial and ethnic backgrounds, including European, Chinese, Japanese, African, and American Indian. Mutations in the HNF1A gene appear to be the most common cause of MODY among adults seen in diabetic clinics.

Ellard (2000) stated that 65 different mutations in the TCF1 gene had been found to cause MODY3 in a total of 116 families worldwide. They noted that diagnostic and predictive genetic testing is possible for the majority of patients with MODY, opening new avenues for the classification, prediction, and perhaps eventually the prevention of diabetes in these families.

Vaxillaire et al. (1995) studied linkage in 12 French MODY families in which diabetes was not genetically linked to previously identified MODY loci. By a genomewide segregation analysis of highly informative microsatellite markers, they localized the gene for a MODY susceptibility locus (MODY3) to 12q in 6 families. The locus in question was thought to lie within a 7-cM interval bracketed by D12S86 and D12S342 (in 12q22-qter). The patients exhibited major hyperglycemia with a severe insulin (176730) secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function.

Lesage et al. (1995) studied the possible implication of the MODY3 locus in late-onset NIDDM. In 600 affected sib pairs from 172 French families, linkage was rejected by all methods of analysis, implying that the MODY gene on 12q is not a major gene in late-onset NIDDM in this population.

Menzel et al. (1995) found evidence of linkage to chromosome 12 in 3 families with MODY from Denmark, Germany, and the U.S. (Michigan) and suggestive evidence of linkage in a family from Japan. They placed the locus in a 5-cM interval between markers D12S86 and D12S807/D12S820. The age of onset of NIDDM was less than 25 years of age in the youngest generation in each pedigree and the segregation was consistent with autosomal dominant inheritance. In 1 pedigree, the body weight of 18 of 22 diabetic subjects was known and only 1 was obese. Diabetes was diagnosed in all but 1 of the subjects before 20 years of age. From the location of the linked markers the MODY3 locus was thought to be in the region 12q24.1-q24.32.

Mahtani et al. (1996) screened over 4,000 individuals from a Swedish-speaking population isolate in western Finland and identified 26 families enriched for NIDDM. Families with the lowest insulin levels showed linkage to 12q24 near D12S1349. Unlike MODY3 families, the Finnish families with low insulin had an age of onset typical for NIDDM (mean = 58 years). Mahtani et al. (1996) inferred the existence of a gene, NIDDM2 (601407), causing noninsulin-dependent diabetes mellitus associated with low insulin secretion and suggested that NIDDM2 and MODY3 may represent different alleles of the same gene.

Yamagata et al. (1996) refined the localization of the MODY3 gene by a combination of genetic mapping and fluorescence in situ hybridization which localized the gene to 12q24.2.

Lehto et al. (1997) analyzed the phenotype of affected members in 4 large Finnish MODY3 kindreds showing linkage to 12q with a maximum lod score of 15. They found evidence of severe impairment in insulin secretion, which was present also in those normal glycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with insulin-dependent diabetes mellitus by lack of glutamic acid decarboxylase antibodies. Taken together with the finding of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM, designated NIDDM2, as demonstrated by Mahtani et al. (1996), the data suggested to Lehto et al. (1997) that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response that subsequently progresses to diabetes, and underlines the importance of subphenotypic classification in studies of diabetes. MODY3 and NIDDM2 may be different alleles of the same gene; NIDDM2 has an average age of onset of 58 years.

{1:Aguilar-Salinas et al. (2001)} investigated possible defects in the insulin sensitivity and the acute insulin response in a group of Mexican patients displaying early-onset NIDDM and evaluated the contribution of mutations in 3 of the genes linked to MODY. They studied 40 Mexican patients diagnosed between 20 and 40 years of age, in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to MODY was carried out by PCR-SSCP. Among this group they found 2 individuals carrying missense mutations in exon 4 of the HNF4A gene and 1 carrying a nonsense mutation in exon 7 of the HNF1A gene; 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. The authors concluded that a defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 years of age. Mutations in either the HNF1A or the HNF4A genes were present among the individuals who developed early-onset diabetes in their population.

Barrio et al. (2002) estimated the prevalence of major MODY subtypes in Spanish MODY families and analyzed genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the GCK (138079), HNF1A, and HNF4A genes using PCR-SSCP and/or direct sequencing. Mutations in MODY genes were identified in 64% of the families. Four pedigrees (18%) harbored mutations in the HNF1A/MODY3 gene, including a previously unreported change. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3 patients. Clinical expression of MODY3 and MODY1 mutations was more severe, including the frequent development of chronic complications.

Molecular basis is known for 612520 because a form of insulin-dependent diabetes mellitus can be caused by heterozygous mutation in the HNF1A gene (142410) on chromosome 12q24.2.

For a phenotypic description and a discussion of genetic heterogeneity of insulin-dependent diabetes mellitus, see IDDM (222100).

Molecular basis is known for 142330 because familial hepatic adenomas can occur through biallelic inactivation of the transcription factor-1 gene (TCF1, HNF1A; 142410) on chromosome 12q24. Hepatic adenomas also occur in high frequency with type I glycogen storage disease (232200).

Molecular basis is known for 600496 because of evidence that maturity-onset diabetes of the young type 3 (MODY3) is caused by mutation in the hepatocyte nuclear factor-1-alpha gene (142410), which maps to chromosome 12q24.2.

MODY is a form of familial noninsulin-dependent diabetes mellitus (NIDDM; 125853) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance. For general information on MODY and on genetic heterogeneity in this disorder, see 606391.

In their review of MODY, Fajans et al. (2001) stated that, not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations in the HNF4A gene (MODY1) and MODY due to mutations in the HNF1A (MODY3) are very similar since HNF4-alpha regulates the expression of HNF1-alpha. Patients with mutations in these genes may present with a mild form of diabetes. Despite similarly mild elevations in fasting plasma glucose concentrations, patients with mutations in HNF4A or HNF1A have significantly higher plasma glucose concentrations 2 hours after glucose administration than do persons with glucokinase mutations. The hyperglycemia in patients with MODY1 and MODY3 tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in may of these patients (30 to 40% require insulin). These forms of MODY are associated with a progressive decrease in insulin secretion. In most populations, mutations in the HNF1A gene are the most common cause of MODY. Patients with MODY1 or MODY3 may have the full spectrum of complications of diabetes. Microvascular complications, particularly those involving the retina or kidneys, are as common in these patients as in patients with type I or type II diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are probably determined by the degree of glycemic control. Patients with MODY1 lose the glucose priming effect of mild hyperglycemia on insulin secretion. Both prediabetic and diabetic persons with mutations in the HNF4A gene secrete decreased amounts of insulin in response to glucose and in response to arginine and also have an impairment of glucagon secretion in response to arginine. Furthermore, a defect in the hypoglycemia-induced secretion of pancreatic polypeptide has been found in prediabetic and diabetic persons who have mutations in the gene for HNF4A. These findings suggested that a deficiency of HNF4A resulting from mutations in this gene may affect the function of the beta, alpha, and pancreatic polypeptide cells within pancreatic islets. Patients with mutations in HNF1A have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria. A deficiency of HNF4A affects triglyceride and apolipoprotein biosynthesis and is associated with a 50% reduction in serum triglyceride concentrations and a 25% reduction in serum concentrations of apolipoproteins AII and CIII and Lp(a).

Fajans et al. (2001) reported that mutations in the HNF1A gene have been identified in all racial and ethnic backgrounds, including European, Chinese, Japanese, African, and American Indian. Mutations in the HNF1A gene appear to be the most common cause of MODY among adults seen in diabetic clinics.

Ellard (2000) stated that 65 different mutations in the TCF1 gene had been found to cause MODY3 in a total of 116 families worldwide. They noted that diagnostic and predictive genetic testing is possible for the majority of patients with MODY, opening new avenues for the classification, prediction, and perhaps eventually the prevention of diabetes in these families.

Vaxillaire et al. (1995) studied linkage in 12 French MODY families in which diabetes was not genetically linked to previously identified MODY loci. By a genomewide segregation analysis of highly informative microsatellite markers, they localized the gene for a MODY susceptibility locus (MODY3) to 12q in 6 families. The locus in question was thought to lie within a 7-cM interval bracketed by D12S86 and D12S342 (in 12q22-qter). The patients exhibited major hyperglycemia with a severe insulin (176730) secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function.

Lesage et al. (1995) studied the possible implication of the MODY3 locus in late-onset NIDDM. In 600 affected sib pairs from 172 French families, linkage was rejected by all methods of analysis, implying that the MODY gene on 12q is not a major gene in late-onset NIDDM in this population.

Menzel et al. (1995) found evidence of linkage to chromosome 12 in 3 families with MODY from Denmark, Germany, and the U.S. (Michigan) and suggestive evidence of linkage in a family from Japan. They placed the locus in a 5-cM interval between markers D12S86 and D12S807/D12S820. The age of onset of NIDDM was less than 25 years of age in the youngest generation in each pedigree and the segregation was consistent with autosomal dominant inheritance. In 1 pedigree, the body weight of 18 of 22 diabetic subjects was known and only 1 was obese. Diabetes was diagnosed in all but 1 of the subjects before 20 years of age. From the location of the linked markers the MODY3 locus was thought to be in the region 12q24.1-q24.32.

Mahtani et al. (1996) screened over 4,000 individuals from a Swedish-speaking population isolate in western Finland and identified 26 families enriched for NIDDM. Families with the lowest insulin levels showed linkage to 12q24 near D12S1349. Unlike MODY3 families, the Finnish families with low insulin had an age of onset typical for NIDDM (mean = 58 years). Mahtani et al. (1996) inferred the existence of a gene, NIDDM2 (601407), causing noninsulin-dependent diabetes mellitus associated with low insulin secretion and suggested that NIDDM2 and MODY3 may represent different alleles of the same gene.

Yamagata et al. (1996) refined the localization of the MODY3 gene by a combination of genetic mapping and fluorescence in situ hybridization which localized the gene to 12q24.2.

Lehto et al. (1997) analyzed the phenotype of affected members in 4 large Finnish MODY3 kindreds showing linkage to 12q with a maximum lod score of 15. They found evidence of severe impairment in insulin secretion, which was present also in those normal glycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with insulin-dependent diabetes mellitus by lack of glutamic acid decarboxylase antibodies. Taken together with the finding of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM, designated NIDDM2, as demonstrated by Mahtani et al. (1996), the data suggested to Lehto et al. (1997) that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response that subsequently progresses to diabetes, and underlines the importance of subphenotypic classification in studies of diabetes. MODY3 and NIDDM2 may be different alleles of the same gene; NIDDM2 has an average age of onset of 58 years.

{1:Aguilar-Salinas et al. (2001)} investigated possible defects in the insulin sensitivity and the acute insulin response in a group of Mexican patients displaying early-onset NIDDM and evaluated the contribution of mutations in 3 of the genes linked to MODY. They studied 40 Mexican patients diagnosed between 20 and 40 years of age, in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to MODY was carried out by PCR-SSCP. Among this group they found 2 individuals carrying missense mutations in exon 4 of the HNF4A gene and 1 carrying a nonsense mutation in exon 7 of the HNF1A gene; 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. The authors concluded that a defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 years of age. Mutations in either the HNF1A or the HNF4A genes were present among the individuals who developed early-onset diabetes in their population.

Barrio et al. (2002) estimated the prevalence of major MODY subtypes in Spanish MODY families and analyzed genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the GCK (138079), HNF1A, and HNF4A genes using PCR-SSCP and/or direct sequencing. Mutations in MODY genes were identified in 64% of the families. Four pedigrees (18%) harbored mutations in the HNF1A/MODY3 gene, including a previously unreported change. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3 patients. Clinical expression of MODY3 and MODY1 mutations was more severe, including the frequent development of chronic complications.

Molecular basis is known for 612520 because a form of insulin-dependent diabetes mellitus can be caused by heterozygous mutation in the HNF1A gene (142410) on chromosome 12q24.2.

For a phenotypic description and a discussion of genetic heterogeneity of insulin-dependent diabetes mellitus, see IDDM (222100).

NP_000050.2:p.Asp1420Tyr in Exon 11 of BRCA2 (NM_000059.3:c.4258G>T)

This is a Missense Variant located in the BRCA2 gene.

This gene has been observed to exhibit Autosomal recessive, Autosomal dominant, and Somatic mutation inheritance pattern.

It has been associated with Fanconi anemia complementation group D1, Wilms tumor, Breast cancer male susceptibility to, Breast-ovarian cancer familial 2, Glioblastoma 3, Medulloblastoma, Pancreatic cancer 2, and Prostate cancer.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.

Molecular basis is known for 605724 because Fanconi anemia complementation group D1 can be caused by homozygous or compound heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q12.

Molecular basis is known for 612555 because susceptibility to familial breast-ovarian cancer-2 (BROVCA2) results from heterozygous germline mutations in the BRCA2 gene (600185) on chromosome 13q12.3.

For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (604370).

For general discussions of breast cancer and ovarian cancer, see 114480 and 167000, respectively.

Molecular basis is known for 613029 because glioma can present as part of a tumor predisposition syndrome caused by germline mutation in the BRCA2 gene (600185) on chromosome 13q12.

For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800).

Molecular basis is known for 613347 because susceptibility to pancreatic cancer is conferred by heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q12.3.

For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.

Molecular basis is known for 605724 because Fanconi anemia complementation group D1 can be caused by homozygous or compound heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q12.

Molecular basis is known for 612555 because susceptibility to familial breast-ovarian cancer-2 (BROVCA2) results from heterozygous germline mutations in the BRCA2 gene (600185) on chromosome 13q12.3.

For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (604370).

For general discussions of breast cancer and ovarian cancer, see 114480 and 167000, respectively.

Molecular basis is known for 613029 because glioma can present as part of a tumor predisposition syndrome caused by germline mutation in the BRCA2 gene (600185) on chromosome 13q12.

For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800).

Molecular basis is known for 613347 because susceptibility to pancreatic cancer is conferred by heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q12.3.

For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350.

NP_000537.3:p.Pro72Arg in Exon 4 of TP53 (NM_000546.5:c.215C>G)

This is a Missense Variant located in the TP53 gene.

Ara et al. (1990) reported that the pro72-to-arg (P72R) change in p53 is caused by polymorphism rather than mutation. Olschwang et al. (1991) assessed the frequency of the pro72-to-arg (P72R) polymorphism and, from its frequency in colon cancer patients and control subjects, concluded that there was no strong association with colon cancer. In both the cancer group and the control group, the frequencies of the pro72 and arg72 alleles were about 31 and 69%, respectively.

The E6 oncoprotein derived from tumor-associated human papillomaviruses (HPVs) binds to and induces degradation of p53. Storey et al. (1998) investigated the effect of the pro72-to-arg polymorphism on susceptibility of p53 to E6-mediated degradation and found that the arg72 form of p53 was significantly more susceptible than the pro72 form. Moreover, allelic analysis of patients with HPV-associated tumors revealed a striking overrepresentation of homozygous arg72 p53 compared with the normal population, indicating that individuals homozygous for arg72 are about 7 times more susceptible to HPV-associated tumorigenesis than heterozygotes.

Using immunoprecipitation followed by SDS-PAGE, Thomas et al. (1999) found that the arg72 and pro72 p53 variants did not differ in their ability to bind DNA in a sequence-specific manner. They concluded that arg72 and pro72 are conformationally indistinguishable and that both can be considered wildtype. However, Thomas et al. (1999) noted that p53(pro) was a stronger inducer of transcription than p53(arg), whereas p53(arg) induced apoptosis faster and was a more potent suppressor of transformation than p53(pro).

Marin et al. (2000) found that some tumor-derived p53 mutants bound and inactivated p73 (601990). The binding of such mutants was influenced by whether TP53 codon 72 encoded arginine or proline. The ability of p53 to bind p73, neutralize p73-induced apoptosis, and transform cells in cooperation with EJ-Ras (see 190020) was enhanced when codon 72 encoded arg. Marin et al. (2000) found that the arg-containing allele was preferentially mutated and retained in squamous cell tumors arising in arg/pro germline heterozygotes. They concluded that inactivation of p53 family members may contribute to the biologic properties of a subset of p53 mutants, and that a polymorphic residue within p53 affects mutant behavior.

Laryngeal papillomatosis is caused by human papillomavirus and is associated with malignant transformation in 3 to 7% of cases. Aaltonen et al. (2001) found no difference in the prevalence of the P72R polymorphism between a group of patients with laryngeal papillomas and a control group.

The pro72-to-arg polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. Dumont et al. (2003) found that in cell lines containing inducible versions of alleles encoding the pro72 and arg72 variants, and in cells with endogenous p53, the arg72 variant induced apoptosis markedly better than the pro72 variant. They suggested that at least 1 source of this enhanced apoptotic potential is the greater ability of the arg72 variant to localize to mitochondria; this localization was accompanied by release of cytochrome c into the cytosol.

In 92 Caucasian MLH1 (120436) or MSH2 (609309) mutation carriers, including 47 with colorectal cancer, Jones et al. (2004) analyzed the p53 codon 72 genotype and found that arg/pro heterozygotes were 1.94 times more likely to get colorectal cancer during any age interval and developed it 13 years earlier than arg/arg homozygotes. The number of pro/pro homozygotes was too small to provide meaningful results.

Kruger et al. (2005) studied the p53 genotype of 167 unrelated patients with hereditary nonpolyposis colon cancer (HNPCC; see 120435) with germline mutations in either MSH2 or MLH1 and found that the median age of onset was 41 years for arg/arg, 36 years for arg/pro, and 32 years for pro/pro individuals (p less than 0.0001). There was no difference in age of onset in 126 patients with microsatellite stable colorectal cancers. Kruger et al. (2005) concluded that in a mismatch repair-deficient background, p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a dose-dependent manner.

Bougeard et al. (2006) studied the effect of the MDM2 SNP309 polymorphism ({164785.0001}) and the arg72-to-pro polymorphism of the p53 gene on cancer risk in 61 French carriers of the p53 germline mutation. The mean age of tumor onset in p53 codon 72 polymorphism arg allele carriers (21.8 years) was different from that of pro/pro patients (34.4 years, p less than 0.05). Bougeard et al. (2006) also observed a cumulative effect of both polymorphisms because the mean ages of tumor onset in carriers of MDM2 G and p53 arg alleles (16.9 years) and those with the MDM2 T/T and p53 pro/pro genotypes (43 years) were clearly different (p less than 0.02). The results confirmed the impact of the MDM2 SNP309 G allele on the age of tumor onset in germline p53 mutation carriers, and suggested that this effect may be amplified by the p53 arg72 allele.

IASPP (607463) is among the most evolutionarily conserved inhibitors of p53, whereas ASPP1 (606455) and ASPP2 (602143) are activators of p53. Bergamaschi et al. (2006) showed that, in addition to the DNA-binding domain, the ASPP family members also bound to the proline-rich region of p53 containing the codon 72 polymorphism. Furthermore, the ASPP family members, particularly IASPP, bound to and regulated the activity of p53 pro72 more efficiently than that of p53 arg72.

Orsted et al. (2007) stated that arg72 increases the ability of p53 to locate to mitochondria and induce cell death, whereas pro72 exhibits lower apoptotic potential but increases cellular arrest in G1 of the cell cycle. In a study of 9,219 Danish individuals, they found that overall 12-year survival was increased in p53 arg/pro heterozygotes by 3% (P of 0.003) and in pro/pro homozygotes by 6% (P of 0.002) compared with arg/arg homozygotes, corresponding to an increase in median survival of 3 years for pro/pro versus arg/arg homozygotes. Pro/pro homozygotes also showed increased survival after development of cancer, or even after development of other life-threatening diseases, compared with arg/arg homozygotes. The arg72-to-pro change was not associated with decreased risk of cancer.

Among 254 patients with glioblastoma multiforme (see 137800), El Hallani et al. (2009) found an association between the pro72 allele and earlier age at onset. The pro/pro genotype was present in 20.6% of patients with onset before age 45 years, compared to in 6.5% of those with onset after age 45 years (p = 0.002) and 5.9% among 238 controls (p = 0.001). The findings were confirmed in an additional cohort of 29 patients. The variant did not have any impact on overall patient survival. Analysis of tumor DNA from 73 cases showed an association between the pro allele and a higher rate of somatic TP53 mutations.

Smoking-Related Accelerated Rate of Decline in Lung Function

In a study of 863 individuals with European grandparents from an unselected New Zealand birth cohort, Hancox et al. (2009) analyzed lung function (FEV1 and FEV1/FVC) between ages 18 and 32 in relation to cumulative history of cigarette smoking and the {dbSNP rs1042522} SNP, and found that the G allele was associated with smoking-related accelerated rate of decline in lung function (608852) (FEV1, p = 0.020; FEV1/FVC, p = 0.037).

The transcription factor p53 responds to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In addition, p53 appears to induce apoptosis through nontranscriptional cytoplasmic processes. In unstressed cells, p53 is kept inactive essentially through the actions of the ubiquitin ligase MDM2 (164785), which inhibits p53 transcriptional activity and ubiquitinates p53 to promote its degradation. Numerous posttranslational modifications modulate p53 activity, most notably phosphorylation and acetylation. Several less abundant p53 isoforms also modulate p53 activity. Activity of p53 is ubiquitously lost in human cancer either by mutation of the p53 gene itself or by loss of cell signaling upstream or downstream of p53 (Toledo and Wahl, 2006; Bourdon, 2007; Vousden and Lane, 2007).

This gene has been observed to exhibit Autosomal recessive, Autosomal dominant, Somatic mutation, and Multifactorial inheritance pattern.

It has been associated with Adrenal cortical carcinoma, Breast cancer, Choroid plexus papilloma, Colorectal cancer, Hepatocellular carcinoma, Li-Fraumeni syndrome, Nasopharyngeal carcinoma, Osteosarcoma, Pancreatic cancer, Basal cell carcinoma 7, and Glioma susceptibility 1.

Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. LFS is characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within an individual, and multiple affected family members. In contrast to other inherited cancer syndromes, which are predominantly characterized by site-specific cancers, LFS presents with a variety of tumor types. The most common types are soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. Classic LFS is defined as a proband with a sarcoma before the age of 45 years and a first-degree relative with any cancer before the age of 45 years and 1 additional first- or second-degree relative in the same lineage with any cancer before the age of 45 years or a sarcoma at any age (Li et al., 1988). Li-Fraumeni-like syndrome (LFL) is defined as a proband with any childhood cancer, or a sarcoma, brain tumor, or adrenocortical tumor before the age of 45 years, plus a first- or second-degree relative in the same lineage with a typical LFS tumor at any age, and an additional first- or second-degree relative in the same lineage with any cancer before the age of 60 years (Birch et al., 1994). A less restrictive definition of LFL is 2 different LFS-related tumors in first- or second-degree relatives at any age (Eeles, 1995). Approximately 70% of LFS cases and 40% of LFL cases contain germline mutations in the p53 gene on chromosome 17p13.1 (Bachinski et al., 2005).

Genetic Heterogeneity of Li-Fraumeni Syndrome

A second form of Li-Fraumeni syndrome (LFS2; 609265) is caused by mutation in the CHEK2 gene (604373), and an LFS locus (LFS3; 609266) has been mapped to chromosome 1q23.

Molecular basis is known for 151623 because Li-Fraumeni syndrome-1 is caused by heterozygous mutation in the p53 gene (TP53; 191170) on chromosome 17p13.1.

Adrenocortical carcinoma (ADCC) is a rare but aggressive childhood tumor, representing about 0.4% of childhood tumors, with a high incidence of associated tumors. ADCC occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome (130650) and is a component tumor in Li-Fraumeni syndrome (LFS; 151623).

Molecular basis is known for 202300 because of evidence that one form of adrenocortical carcinoma is caused by heterozygous mutation in the TP53 gene (191170) on chromosome 17p13.

Choroid plexus tumors are of neuroectodermal origin and range from benign choroid plexus papillomas (CPPs) to malignant choroid carcinomas (CPCs). These rare tumors generally occur in childhood, but have also been reported in adults. Patients typically present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures (summary by Safaee et al., 2013).

Molecular basis is known for 260500 because of evidence that one form of choroid plexus papilloma (CPP) results from heterozygous mutation in the p53 gene (TP53; 191170) on chromosome 17p13.

Molecular basis is known for 614740 because susceptibility to basal cell carcinoma (BCC7) is influenced by variation in the TP53 gene (191170) on chromosome 17p13.1.

For a general phenotypic description and a discussion of genetic heterogeneity of basal cell carcinoma, see BCC1 (605462).

Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. LFS is characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within an individual, and multiple affected family members. In contrast to other inherited cancer syndromes, which are predominantly characterized by site-specific cancers, LFS presents with a variety of tumor types. The most common types are soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. Classic LFS is defined as a proband with a sarcoma before the age of 45 years and a first-degree relative with any cancer before the age of 45 years and 1 additional first- or second-degree relative in the same lineage with any cancer before the age of 45 years or a sarcoma at any age (Li et al., 1988). Li-Fraumeni-like syndrome (LFL) is defined as a proband with any childhood cancer, or a sarcoma, brain tumor, or adrenocortical tumor before the age of 45 years, plus a first- or second-degree relative in the same lineage with a typical LFS tumor at any age, and an additional first- or second-degree relative in the same lineage with any cancer before the age of 60 years (Birch et al., 1994). A less restrictive definition of LFL is 2 different LFS-related tumors in first- or second-degree relatives at any age (Eeles, 1995). Approximately 70% of LFS cases and 40% of LFL cases contain germline mutations in the p53 gene on chromosome 17p13.1 (Bachinski et al., 2005).

Genetic Heterogeneity of Li-Fraumeni Syndrome

A second form of Li-Fraumeni syndrome (LFS2; 609265) is caused by mutation in the CHEK2 gene (604373), and an LFS locus (LFS3; 609266) has been mapped to chromosome 1q23.

Molecular basis is known for 151623 because Li-Fraumeni syndrome-1 is caused by heterozygous mutation in the p53 gene (TP53; 191170) on chromosome 17p13.1.

Adrenocortical carcinoma (ADCC) is a rare but aggressive childhood tumor, representing about 0.4% of childhood tumors, with a high incidence of associated tumors. ADCC occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome (130650) and is a component tumor in Li-Fraumeni syndrome (LFS; 151623).

Molecular basis is known for 202300 because of evidence that one form of adrenocortical carcinoma is caused by heterozygous mutation in the TP53 gene (191170) on chromosome 17p13.

Choroid plexus tumors are of neuroectodermal origin and range from benign choroid plexus papillomas (CPPs) to malignant choroid carcinomas (CPCs). These rare tumors generally occur in childhood, but have also been reported in adults. Patients typically present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures (summary by Safaee et al., 2013).

Molecular basis is known for 260500 because of evidence that one form of choroid plexus papilloma (CPP) results from heterozygous mutation in the p53 gene (TP53; 191170) on chromosome 17p13.

Molecular basis is known for 614740 because susceptibility to basal cell carcinoma (BCC7) is influenced by variation in the TP53 gene (191170) on chromosome 17p13.1.

For a general phenotypic description and a discussion of genetic heterogeneity of basal cell carcinoma, see BCC1 (605462).