Submissions for variant NM_000077.5(CDKN2A):c.35C>A (p.Ser12Ter)

dbSNP: rs141798398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775634	SCV000909998	pathogenic	Hereditary cancer-predisposing syndrome	2018-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817300	SCV000957852	pathogenic	Familial melanoma	2023-03-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 630390). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 17055252, 27083775, 28830827). This sequence change creates a premature translational stop signal (p.Ser12*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000817300	SCV002041872	pathogenic	Familial melanoma	2021-11-12	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.35C>A (p.Ser12X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 234484 control chromosomes (gnomAD and publication data). c.35C>A has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Casula_2004, Seifert_2016, Taylor_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000775634	SCV002617379	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-09	criteria provided, single submitter	clinical testing	The p.S12* pathogenic mutation (also known as c.35C>A), located in coding exon 1 of the CDKN2A gene, results from a C to A substitution at nucleotide position 35. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration has been reported in patients affected with melanoma (Casula M et al. J Clin Oncol, 2004 Jan;22:286-92; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Taylor NJ et al. J Invest Dermatol, 2017 12;137:2606-2612). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003396344	SCV004103601	pathogenic	CDKN2A-related disorder	2023-11-03	criteria provided, single submitter	clinical testing	The CDKN2A c.35C>A variant is predicted to result in premature protein termination (p.Ser12*). This variant corresponds to c.35C>A (p.Ser*) in both p16INK4A (NM_000077.4) and p14ARF (NM_058195.3). This variant has been reported in individuals with cutaneous malignant melanoma (Table 1, Casula et al. 2007. PubMed ID: 17055252; Table 1, Casula et al. 2009. PubMed ID: 19799798; Table S3, Taylor et al. 2017. PubMed ID: 28830827). It has also been reported in an individual with a personal history of breast cancer and multiple melanomas (Table 2, Seifert et al. 2016. PubMed ID: 27083775). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/630390/). Nonsense variants in CDKN2A are expected to be pathogenic. This variant is interpreted as pathogenic.