Submissions for variant NM_000077.5(CDKN2A):c.377T>A (p.Val126Asp)

dbSNP: rs104894098

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212403	SCV000210946	pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition, sub-cellular localization, and CDK4 and CDK6 binding (Parry 1996, Becker 2001, McKenzie 2010, Miller 2011, Jenkins 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as Val118Asp; This variant is associated with the following publications: (PMID: 9425228, 15146471, 15304099, 23371019, 10389768, 23190892, 7566978, 11595726, 21462282, 7987388, 7666916, 11506491, 11008905, 16905682, 16893909, 12925390, 11807902, 17492760, 26694476, 20340136, 7647780, 8668202, 27473757, 28060055, 25356972, 29541281, 29215650, 30113427, 31567591, 22841127, 18983535, 26225579, 33555482, 33766116, 34573422, 16169933, 7987387)
Ambry Genetics	RCV000160413	SCV000212759	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	The p.V126D pathogenic mutation (also known as c.377T>A), located in coding exon 2 of the CDKN2A gene, results from a T to A substitution at nucleotide position 377. The valine at codon 126 is replaced by aspartic acid, an amino acid with highly dissimilar properties. Data supports p.V126D as a North American founder mutation (Goldstein AM et al. Br. J. Cancer, 2001 Aug;85:527-30). It is well documented in families with hereditary melanoma (Hussussian CJ et al. Nat. Genet. 1994 Sep;8(1):15-21; Parry D and Peters G. Mol. Cell. Biol. 1996 Jul;16(7):3844-52; Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305; Becker TM et al. Clin. Cancer. Res. 2001 Oct;7:3282; Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11) and has also been identified in a familial pancreatic cancer kindred with no melanoma history (Cremin C et al. Hered Cancer Clin Pract, 2018 Mar;16:7). Functional studies have shown this alteration exhibits significantly decreased CDK4/CDK6 affinity and impaired cell cycle regulation (Ranade K et al. Nat. Genet. 1995 May;10(1):114-6; McKenzie HA et al. Hum. Mut. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51). Of note, this alteration is also designated as p.Val118Asp (p.V118D) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227154	SCV000283447	pathogenic	Familial melanoma	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 126 of the CDKN2A (p16INK4a) protein (p.Val126Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 7987387, 9425228, 15146471, 16905682, 20340136, 23371019, 25356972). It has also been observed to segregate with disease in related individuals. This variant is also known as Val118Asp. ClinVar contains an entry for this variant (Variation ID: 9420). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 7647780, 8668202, 10389768, 11595726, 20340136, 23190892). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000576733	SCV000677726	pathogenic	Melanoma-pancreatic cancer syndrome	2016-12-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160413	SCV000684526	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces valine with aspartic acid at codon 126 in the fourth ankyrin repeat of the CDKN2A (p16INK4A) protein. This variant is also known as p.Val118Asp in the literature. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant impairs p16INK4A binding to CDK4 and CDK6 (PMID: 7647780, 8668202, 11595726, 20340136) and disrupts subcellular localization (PMID: 10389768, 20340136), and cell cycle regulation (PMID: 8668202, 11595726, 20340136, 23190892, 35001868). This variant has been reported in over twenty individuals affected with familial melanoma (PMID: 9425228, 11506491, 20340136, 26225579, 21614589, 23371019, 25685612) and in over ten individuals affected with pancreatic cancer (PMID: 15146471, 25356972, 29541281). This variant has been shown to segregate with disease in two families affected with melanoma (PMID: 7987387). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000576733	SCV002012419	pathogenic	Melanoma-pancreatic cancer syndrome	2021-10-11	criteria provided, single submitter	clinical testing	The CDKN2A c.377T>A (p.Val126Asp) missense change replaces valine with aspartic acid at codon 126 of the CDKN2A gene and is absent in population databases including gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant is one of the most common pathogenic variants found in melanoma-prone families (PMID: 21249757). It has been reported in over twenty individuals affected with familial melanoma (PS4; PMID: 9425228, 11506491, 20340136, 21614589, 23371019, 25685612, 26225579) and been shown to segregate with disease in two families affected with melanoma (PP1; PMID: 7987387). In addition, it has been reported in multiple individuals affected with pancreatic cancer (PMID: 15146471, 25356972, 29541281) and in an individual with osteosarcoma where the tumor was found to be homozygous for the variant (PP4; internal data). Five of six in silico tools predict a deleterious effect of this variant on protein function (PP3), and in vitro functional assays have shown that this variant impairs cell cycle inhibition and binding affinity to CDK4 and CDK6 (PS3; PMID: 7566978, 7647780, 8668202, 11595726, 20340136, 21462282, 23190892). This variant is also known as p.Val118Asp in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied: PS3, PS4, PM2_supporting, PP1, PP3, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000227154	SCV002600886	pathogenic	Familial melanoma	2022-10-05	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.377T>A (p.Val126Asp), also known as p.Val118Asp, results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244452 control chromosomes (gnomAD). c.377T>A has been reported in the literature segregating with disease in multiple individuals affected with Malignant Melanoma (e.g. Kamb_1994, Hussussian_1994). These data indicate that the variant is very likely to be associated with disease. In vitro assays revealed that the variant had reduced binding affinity and ability to inhibit cyclin D1/CDK4 activity, and complete inability to bind/inhibit cyclin D1/CDK6 activity (Ranade_1995). Additionally, transcriptomic analysis of skin fibroblasts revealed there were consistent shifts in gene expression profiles between carriers and controls (Fan_2013). Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482853	SCV002777576	pathogenic	Melanoma-pancreatic cancer syndrome; Melanoma, cutaneous malignant, susceptibility to, 2; Melanoma and neural system tumor syndrome	2021-11-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576733	SCV004018549	pathogenic	Melanoma-pancreatic cancer syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7987387, 7987388].
Baylor Genetics	RCV003473078	SCV004212494	pathogenic	Melanoma and neural system tumor syndrome	2023-08-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212403	SCV004221641	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with melanoma and pancreatic cancer (PMIDs: 22841127 (2012), 18983535 (2008), 16905682 (2007), 15146471 (2004), 9425228 (1998)). Functional studies showed that the variant impacts protein function (PMIDs: 23190892 (2013), 20340136 (2010), 11595726 (2001), 10389768 (1999)). Additionally, the variant has been reported to segregate with melanoma in several affected families (PMID: 7987387 (1994)). Based on the available information, this variant is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000576733	SCV004812083	pathogenic	Melanoma-pancreatic cancer syndrome	2024-03-20	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM2_SUP,PP1,PP4
OMIM	RCV000010027	SCV000030248	risk factor	Melanoma, cutaneous malignant, susceptibility to, 2	2008-05-01	no assertion criteria provided	literature only