ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.379G>C (p.Ala127Pro) (rs6413464)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693116 SCV000820971 uncertain significance Hereditary melanoma 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 127 of the CDKN2A (p16INK4a) protein (p.Ala127Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs6413464, ExAC 0.002%). This variant has been reported in individuals and families affected with melanoma and pancreatic cancer (PMID: 11815963, 18983535,21462282, 18023021, 22804906). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 RCV001021177 SCV001182758 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-04 criteria provided, single submitter clinical testing The p.A127P variant (also known as c.379G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 379. The alanine at codon 127 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in numerous kindreds with familial melanoma and/or pancreatic cancer (Lynch HT, et al. Cancer 2002 Jan; 94(1):84-96; Pastorino L, et al. Pigment Cell Melanoma Res 2008 Dec; 21(6):700-9; Helsing P, et al. Genes Chromosomes Cancer 2008 Feb; 47(2):175-84; Levin T et al. Fam. Cancer, 2017 04;16:257-265). In one such family, the alteration was found to segregate with disease in three of three family members tested (Lynch HT, et al. Cancer 2002 Jan; 94(1):84-96). 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 poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001021177 SCV001349018 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 127 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Although functional studies have not been reported for this variant, a structural analysis by an external laboratory indicates that this variant is likely to result in a significant decrease in structural stability of the protein (ClinVar SCV001182758.2). This variant has been reported in at least ten individuals affected with melanoma (PMID: 11815963, 18023021, 18983535, 21462282, 22804906, 26775776, 27804060, 30274933) and pancreatic cancer (PMID: 11815963; Color data). Positive family history has been reported for most of these individuals. This variant has been shown to segregate with disease in a family affected with late-onset pancreatic cancer and cutaneous malignant melanoma (3 informative meiosis, PMID: 11815963). This variant is rare in the general population and has been identified in 1/244500 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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