ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.377T>A (p.Val126Asp) (rs104894098)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160413 SCV000212759 pathogenic Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Color RCV000160413 SCV000684526 pathogenic Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000576733 SCV000677726 pathogenic Melanoma-pancreatic cancer syndrome 2016-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000212403 SCV000210946 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted CDKN2A c.377T>A at the cDNA level, p.Val126Asp (V126D) at the protein level, and results in the change of a Valine to an Aspartic Acid (GTC>GAC). This variant, also published as CDKN2A c.371T>A and p.Val118Asp due to the use of different reference sequence, has been observed in multiple familial melanoma kindreds and has been reported as the most commonly observed pathogenic CDKN2A variant in North American melanoma-prone families (Hussussian 1994, Kamb 1994, Goldstein 1995, Soufir 1998, Goldstein 2000, Goldstein 2001, Miller 2011, Mangas 2016, Borroni 2017). Additionally, in vitro functional assays have shown that CDKN2A Val126Asp impairs the cell cycle inhibition function as well as CDK4 and CDK6 binding affinity (Parry 1996, Becker 2001, McKenzie 2010, Miller 2011, Jenkins 2013). CDKN2A Val126Asp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Val126Asp occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the ANK 4 repeat (UniProt). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000227154 SCV000283447 pathogenic Hereditary cutaneous melanoma 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 126 of the CDKN2A (p16INK4a) protein (p.Val126Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many families and individuals affected with melanoma and/or pancreatic cancer (PMID: 7987387, 9425228, 15146471, 16905682, 20340136, 23371019, 25356972). This variant was reported to segregate with disease in at least one of these families (PMID: 7987387). This variant is also known as Val118Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 9420). Experimental studies have shown that this missense change results in impaired CDK4 and CDK6 binding (PMID: 7647780, 8668202, 11595726, 20340136), altered sub-cellular localization (PMID: 10389768, 20340136), and disrupted cell cycle regulation (PMID: 8668202, 11595726, 20340136, 23190892). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000010027 SCV000030248 risk factor Cutaneous malignant melanoma 2 2008-05-01 no assertion criteria provided literature only

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