Submissions for variant NM_000077.5(CDKN2A):c.170C>T (p.Ala57Val)

dbSNP: rs372266620

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079843	SCV000261199	likely benign	Familial melanoma	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215562	SCV000274603	likely benign	Hereditary cancer-predisposing syndrome	2018-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000587917	SCV000292536	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma and/or pancreatic cancer (Soufir 1998, Soufir 2004, Begg 2005, Orlow 2007, Kannengiesser 2009, Spica 2011); Published functional demonstrate normal or partial binding to CDK4 and elevated levels of reactive oxygen species (Kannengiesser et al., 2009; Jenkins et al., 2013; Li et al., 2022); This variant is associated with the following publications: (PMID: 12752119, 14735200, 21507037, 20707869, 21462282, 9425228, 19260062, 23190892, 9823374, 25980754, 26104880, 16234564, 17218939, 18335566, 18023021, 10596908, 18573309, 19375815, 9132280, 24728327, 21085193, 28440912, 28188106, 27882345, 26664139, 18509008, 16354195, 16896043, 26286987, 28135145, 15146471, 25186627, 29958927, 29769011, 33076392, 35001868, 34369425, 35029067, 18178632)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587917	SCV000601019	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in affected individuals with melanoma and colorectal cancer (PMIDs: 9425228 (1998), 16234564 (2005), 18178632 (2008), 21462282 (2011), and 28135145 (2017)). Functional studies have shown that this variant causes partial loss of CDK4 binding, elevated levels of reactive oxygen species, but had a mild effect on cell proliferation and cell cycle regulation (PMIDs: 19260062 (2009) and 23190892 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317152	SCV000695335	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.170C>T (p.Ala57Val) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 242428 control chromosomes (gnomAD, Bodian_2014, Goldstein_2008, Xu_2015). This frequency is not significantly higher than estimated for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (9.5e-05 vs 0.0003), allowing no conclusion about variant significance. c.170C>T has been identified in multiple melanoma patients (e.g. Begg_2005, Goldstein_2008, Kannengiesser_2009, Orlow_2007, Soufir_1998, Soufir_2004), one of whom also had pancreatic cancer (Soufir_2004), as well as in one acute lymphoblastic leukaemia patient (Xu_2015), and in one pancreatic cancer patient without melanoma (Zhu_2021). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Experimental studies have shown that this missense change can partially bind CDK4, resulting in elevated levels of reactive oxygen species, while retaining the cell cycle arrest function (Jenkins 2013, Kannengiesser 2009). The clinical significance of elevated levels of reactive oxygen species (ROS) compared to wild-type p16 is unknown. A subsequent study which applied a computational methodology combining functional data from a cell cycle assay, as well as epidemiological and prediction data, classified this variant as having uncertain significance (Miller 2011). The variant was also shown to effectively suppress leukemic transformation in p16Ink4a deficient mouse cells, to similar levels seen with wild-type (Li_2022). Together, these results show no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 16234564, 24728327, 27756164, 27960642, 28765326, 18178632, 23190892, 19260062, 9166859, 34369425, 21462282, 16818274, 18519632, 17218939, 7718873, 14735200, 9425228, 26104880, 33939675). Nine ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000215562	SCV000910726	benign	Hereditary cancer-predisposing syndrome	2016-07-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000988157	SCV001137774	benign	Melanoma-pancreatic cancer syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587917	SCV002010648	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000215562	SCV002534313	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000988157	SCV004171402	uncertain significance	Melanoma-pancreatic cancer syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The CDKN2A c.170C>T (p.Ala57Val) missense change has a maximum founder subpopulation frequency of 0.013% and a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in an individual with pancreatic cancer and melanoma (PMID: 14735200). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004754357	SCV000805822	uncertain significance	CDKN2A-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The CDKN2A c.170C>T variant is predicted to result in the amino acid substitution p.Ala57Val. This variant has been reported in several individuals or families with melanoma (Soufir et al. 2004. PubMed ID: 14735200; Begg et al. 2005. PubMed ID: 16234564; Orlow et al. 2007. PubMed ID: 17218939). However, in at least one family, the variant did not segregate with disease (Kannengiesser et al. 2009. PubMed ID: 19260062). In addition, another study found that the incidence of the variant was the same in cases (4/776) versus controls (4/827) (Goldstein et al. 2008. PubMed ID: 18178632). Functional studies suggest that this variant only partially impairs CDK4 binding but does result in reduced suppression of reactive oxygen species (Kannengiesser et al. 2009. PubMed ID: 19260062; Jenkins et al. 2013. PubMed ID: 23190892). This variant is reported in 0.013% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has been classified as benign, likely benign, and uncertain by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220562/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.