Submissions for variant NM_000077.5(CDKN2A):c.104G>C (p.Gly35Ala)

gnomAD frequency: 0.00001  dbSNP: rs746834149

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551714	SCV000637388	pathogenic	Familial melanoma	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 35 of the CDKN2A (p16INK4a) protein (p.Gly35Ala). This variant is present in population databases (rs746834149, gnomAD 0.003%). This missense change has been observed in individual(s) with melanoma (PMID: 8595405, 9425228, 12072543, 12556369, 19260062, 19759551, 21462282, 22841127; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 98G>C (Gly27Ala). ClinVar contains an entry for this variant (Variation ID: 463481). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 14745721, 19260062, 20340136, 23190892, 24659262). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001017130	SCV001178162	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	The p.G35A pathogenic mutation (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 observed in multiple individuals with a personal and/or family history that is consistent with CDKN2A-related disease (Ambry internal data). This alteration has been identified in numerous cutaneous melanoma kindreds and was found to segregate with disease in multiple families (Ambry internal data; 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; Byeon IJ et al. Mol Cell 1998 Feb;1(3):421-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001017130	SCV001349023	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 35 in the ankyrin repeat 1 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.
GeneDx	RCV001584269	SCV001819548	uncertain significance	not provided	2022-07-05	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; Observed in individuals with a personal or family history of melanoma (Walker et al., 1995; Soufir et al., 1998; Hearle et al., 2003; Cust et al., 2011; Maxwell et al., 2015); Published functional studies demonstrate reduced ability to bind to CDK4 and CDK6 and altered subcellular localization in some assays, while others showed much higher residual CDK4 binding, intermediate levels of cell proliferation arrest, and no impairment in oxidative or cell cycle function (Kannengiesser et al., 2009; McKenzie et al., 2010; Jenkins et al., 2013; Scaini et al., 2014); This variant is associated with the following publications: (PMID: 26206799, 9425228, 19260062, 24659262, 16905682, 10070944, 9132280, 15146471, 25780468, 18573309, 12556369, 12072543, 28440912, 9823374, 20340136, 23190892, 21462282, 9416844, 25503501, 21325014, 11500805, 8595405, 22841127, 28830827, 17047042, 14745721, 9653180, 9529249, 16173922)
Sema4, Sema4	RCV001017130	SCV002534302	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation