ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.104G>C (p.Gly35Ala) (rs746834149)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551714 SCV000637388 uncertain significance Hereditary melanoma 2020-08-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 35 of the CDKN2A (p16INK4a) protein (p.Gly35Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. While this variant is present in population databases (rs746834149), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been identified in individuals and families affected with melanoma. In one family, this variant was shown to segregate with disease (PMID: 8595405, 9425228, 12072543, 12556369, 17047042, 19260062, 19759551, 20340136, 22841127). This variant has also been identified in an individual affected with breast cancer (PMID: 25503501). This variant is also known as 98G>C (Gly27Ala) in the literature (PMID: 8595405). ClinVar contains an entry for this variant (Variation ID: 463481). Experimental in vitro studies do not agree on the deleterious nature of this change on CDKN2A (p16INK4a) protein function (PMID: 14745721, 19260062, 20340136, 23190892, 24659262). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001017130 SCV001178162 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-30 criteria provided, single submitter clinical testing The p.G35A variant (also known as c.104G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 104. The glycine at codon 35 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in numerous cutaneous melanoma kindreds and was found to segregate with disease in at least one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Soufir N et al. Hum. Mol. Genet. 1998 Feb;7:209-16; Goldstein AM et al. Cancer Res. 2006 Oct;66:9818-28). It has also been identified in an individual with uveal melanoma (Hearle N et al. Invest. Ophthalmol. Vis. Sci. 2003 Feb;44:458-62). In the majority of functional assays, the p.G35A mutant demonstrates partially deficient CDK4 binding ability, cellular localization, and cell proliferation (Ghiorzo P et al. Hum. Pathol. 2004 Jan;35:25-33; Kannengiesser C et al. Hum. Mutat. 2009 Apr;30:564-74; McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701; Scaini MC et al. Hum. Mutat. 2014 Jul;35:828-40); however, in oxidative function and cell cycle assays, p.G35A retained wild type function (Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133:1043-51). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry Internal Data). This amino acid position is highly conserved in available vertebrate species. This alteration has also been observed individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data). 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.
Color Health, Inc RCV001017130 SCV001349023 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This missense variant replaces glycine with alanine at codon 35 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein exhibits reduced CDK4 and CDK6 binding (PMID: 19260062, 20340136) and partially impaired capacity to inhibit cell proliferation (PMID: 19260062, 23190892, 24659262). This variant has been reported in many individuals affected with melanoma (PMID: 8595405, 9425228, 12072543, 12556369, 17047042, 19260062, 20340136, 22841127, 28830827) and in an individual affected with breast cancer and sarcoma (PMID: 25503501). This variant has also been identified in 3/244916 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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