Submissions for variant NM_000077.5(CDKN2A):c.176T>G (p.Val59Gly)

dbSNP: rs104894099

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409228	SCV000489045	likely pathogenic	Melanoma-pancreatic cancer syndrome	2016-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000494082	SCV000581514	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-19	criteria provided, single submitter	clinical testing	The p.V59G variant (also known as c.176T>G), located in coding exon 2 of the CDKN2A gene, results from a T to G substitution at nucleotide position 176. The valine at codon 59 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in several families with multiple cases of melanoma and/or pancreatic cancer (Puig S et al. J. Clin. Oncol. 2005 May;23:3043-51; Pedace L et al. Cancer Epidemiol. 2011 Dec;35:e116-20; Nagore E et al. Melanoma Res. 2009 Aug;19:211-4; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Earl J et a. EBioMedicine 2020 Mar;53:102675; De Simone P et al. Int J Mol Sci, 2020 Dec;21:). One study described this alteration in four families with multiple cases of melanoma and determined that it may be a founder mutation of Mediterranean origin (Yakobson E et al. Eur. J. Hum. Genet. 2003 Apr;11:288-96). Based on the results of protein–protein interaction and cell proliferation assays, the authors concluded that this alteration likely impairs p16 protein function, but may be only a moderate dysfunction mutation. Notably, there were several unaffected p.V59G carriers identified in these four families. In addition, one individual diagnosed with melanoma at age 36 was found to be homozygous for this alteration (Yakobson E et al. Eur. J. Hum. Genet. 2003 Apr;11:288-96). This alteration has also been reported in pancreatic cancer patients (Lowery MA et al. J. Natl. Cancer Inst., 2018 10;110:1067-1074; Earl J et al. EBioMedicine, 2020 Mar;53:102675), including in a patient with a rare tumor type of adenosquamous pancreatic carcinoma (ASPC) (Martínez de Juan F et al. World J Gastrointest Oncol. 2017 Sep;9:390-396). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545232	SCV000637399	pathogenic	Familial melanoma	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 59 of the CDKN2A (p16INK4a) protein (p.Val59Gly). This variant is present in population databases (rs104894099, gnomAD 0.003%). This missense change has been observed in individuals with melanoma (PMID: 9425228, 12700603, 15146471, 19571771, 19799798, 20653773, 21893440, 22841127, 26681309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9423). 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: 12700603). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000494082	SCV000684515	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-03	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 glycine at codon 59 of the CDKN2A (p16INK4A) protein. 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 the mutant protein to exhibit defective binding to CDK4 and CDK6, and reduced ability to suppress cell proliferation (PMID: 12700603, 19260062). This variant has been observed in many individuals and families affected with melanoma (PMID: 9036865, 9425228, 10874641, 12700603, 14646620, 19260062, 19571771, 20653773, 21893440, 22841127, 25780468, 26681309, 29543703, 32455486, 35566480) and shown to segregate with melanoma in three unrelated families (PMID: 12700603). This variant has also been reported in an individual affected with familial pancreatic cancer (PMID: 32113160). This variant has been identified in 1/219096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800291	SCV002046102	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	This variant has been reported as individuals and families with melanoma and pancreatic cancer in the published literature (PMID: 9425228 (1998), 22841127 (2012), 26681309 (2016), 29506128 (2018), 29543703 (2018), and 32113160 (2020)). A peer-reviewed experimental study has reported a damaging effect of the variant on p16 protein function (PMID: 12700603 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000545232	SCV002571091	pathogenic	Familial melanoma	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.176T>G (p.Val59Gly) results in a non-conservative amino acid change located in the second ankyrin repeat domain (Soufir_1998) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-06 in 219096 control chromosomes. c.176T>G has been reported in the literature in multiple individuals from families affected with sporadic/Cutaneous Malignant Melanoma ((example, Piccinin_1997, Soufir_1998, Yakobson_2003, Puig_2005, Casula_2007, de Torre_2010, De Unamuno_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro (example, Yakobson_2003). The most pronounced variant effect results in moderate levels of dysfunction as measured by ability to interact with CDK4 and CDK6 as well as its ability to inhibit the proliferation of human diploid fibroblasts. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001800291	SCV002571347	likely pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: reduced binding with CDK4 and CDK6 and a moderate impact on cell proliferation (Yacobson et al., 2003; Kannengiesser et al., 2009); This variant is associated with the following publications: (PMID: 15150307, 29506128, 9425228, 25780468, 19571771, 26681309, 21893440, 19260062, 22841127, 19799798, 10874641, 15860862, 16905682, 12700603, 9823374, 28873162, 28717660, 15146471, 16470311, 17492760, 17055252, 29543703, 31589614, 33237286, 28979722, 20653773, 32113160, 34072659, 33322357)
MGZ Medical Genetics Center	RCV000010030	SCV002581087	likely pathogenic	Melanoma, cutaneous malignant, susceptibility to, 2	2022-07-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496319	SCV002813852	pathogenic	Melanoma-pancreatic cancer syndrome; Melanoma, cutaneous malignant, susceptibility to, 2; Melanoma and neural system tumor syndrome	2021-12-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473079	SCV004212523	likely pathogenic	Melanoma and neural system tumor syndrome	2023-01-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001800291	SCV004702118	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CDKN2A: PP1:Strong, PM2, PS4:Moderate, PS3:Supporting, BP4
Genetics Department, Catlab	RCV000409228	SCV005419262	likely pathogenic	Melanoma-pancreatic cancer syndrome	2024-09-04	criteria provided, single submitter	clinical testing	The c.176T>G variant in the CDKN2A gene has been previously found in at least 4 independent families with several affected members where it segregated (PMID:12700603) (PS4_Moderate, PP1) and the variant has an extremely low frequence in gnomAD 4.0 (AF= 1.8e-06) (PM2). Functional studies have shown that the variant alters the function of p16INK4a (PMID: 12700603) (PS3_Moderate). The REVEL value is 0.189 (BP4). With all the available evidence, the variant is classified as likely pathogenic.
OMIM	RCV000010030	SCV000030251	risk factor	Melanoma, cutaneous malignant, susceptibility to, 2	2003-04-01	no assertion criteria provided	literature only