Submissions for variant NM_000077.5(CDKN2A):c.251A>C (p.Asp84Ala)

dbSNP: rs587782792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132342	SCV000187431	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-15	criteria provided, single submitter	clinical testing	The p.D84A variant (also known as c.251A>C), located in coding exon 2 of the CDKN2A gene, results from an A to C substitution at nucleotide position 251. The aspartic acid at codon 84 is replaced by alanine, an amino acid with dissimilar properties. This variant has been identified in numerous families with clinical histories that are consistent with a familial melanoma syndrome (Orlow I et al. J Mol Diagn, 2001 Nov;3:158-63; Harland M et al. Hered Cancer Clin Pract, 2014 Nov;12:20; Harland M et al. Genes Chromosomes Cancer, 2005 Jun;43:128-36; Cust AE et al. J. Med. Genet., 2011 Apr;48:266-72; Demenais F et al. J. Natl. Cancer Inst., 2010 Oct;102:1568-83; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Niendorf KB et al. J. Med. Genet., 2006 Jun;43:501-6; Ambry internal data). In addition, this amino acid sits at the interface with CDK6 and is anticipated to result in decreased binding affinity (Yuan C et al. Protein Sci., 2000 Jun;9:1120-8; Ambry internal data). A functional study reported this variant as deleterious based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 01;11). Another alteration at the same codon, p.D84N (c.250G>A), has been detected in a Slovenian patient with multiple primary cutaneous melanomas (CM) who has no family history and in a French patient with a CM who has a first-degree relative with a CM (Peric B, BMC Med. Genet. 2008 ; 9():86; Maubec E, J. Am. Acad. Dermatol. 2012 Dec; 67(6):1257-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000236474	SCV000292885	likely pathogenic	not provided	2024-05-26	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; This variant is associated with the following publications: (PMID: 20876876, 16169933, 25780468, 11687599, 21325014, 15761864, 10498896, 21462282, 28615371, 35001868)
PreventionGenetics, part of Exact Sciences	RCV000236474	SCV000805823	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with cutaneous melanoma (see for example, Table 2, Orlow et al. 2001. PubMed ID: 11687599; Figure 2, Niendorf et al. 2005. PubMed ID: 16169933; Table 1, Miller et al. 2011. PubMed ID: 21462282). This variant has not been reported in a large population database, indicating it is rare. An in vitro experimental study using multiple cell lines suggests this variant increases cell proliferation (Table S2, Kimura et al. 2022. PubMed ID: 35001868). This variant has been classified as pathogenic/likely pathogenic by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142882/). Alternate nucleotide substitutions affecting the same amino acid (p.Asp84Tyr, p.Asp84Asn, and p.Asp84Val) have been reported in multiple individuals with cutaneous melanoma (see for example, Table 2, Ruiz et al. 1999. PubMed ID: 10874641; Table 2, Maubec et al. 2012. PubMed ID: 22841127; Table 3, Borroni et al. 2017. PubMed ID: 28060055). In summary, the c.251A>C (p.Asp84Ala) variant is interpreted as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687345	SCV000814908	likely pathogenic	Familial melanoma	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial cutaneous melanoma (PMID: 11687599, 15761864, 16169933, 20876876, 21462282; Invitae). ClinVar contains an entry for this variant (Variation ID: 142882). 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: 35001868). This variant disrupts the p.Asp84 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10491434, 21462282, 28060055). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003474789	SCV004212509	likely pathogenic	Melanoma and neural system tumor syndrome	2023-06-21	criteria provided, single submitter	clinical testing