Submissions for variant NM_000077.5(CDKN2A):c.238C>T (p.Arg80Ter)

dbSNP: rs121913388

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001186483	SCV001352917	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the CDKN2A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV001588807	SCV001816397	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8668202, 11687599, 8153634, 29152076, 10854221, 15195137, 18205010, 27415609, 29917141, 23939042, 31775759, 30039340, 9529249, 9653180, 16173922, 31382929)
AiLife Diagnostics, AiLife Diagnostics	RCV001588807	SCV002502778	likely pathogenic	not provided	2021-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001186483	SCV002731933	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	clinical testing	The p.R80* pathogenic mutation (also known as c.238C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 238. This changes the amino acid from an arginine to a stop codon within coding exon 2. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512955	SCV003440878	pathogenic	Familial melanoma	2023-07-19	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. ClinVar contains an entry for this variant (Variation ID: 9409). This variant is also known as c.281C>T p.Pro94Leu in the CDKN2A (p14ARF) transcript. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 31382929). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg80*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002512955	SCV003845134	pathogenic	Familial melanoma	2023-02-23	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.238C>T (p.Arg80X) 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. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 229380 control chromosomes (gnomAD). c.238C>T has been reported in the literature in individuals affected with Multiple Primary Melanomas (Puig_2015, Casula_2019). At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in loss of binding to Cdk4 and Cdk6 (Parry_1996). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000010012	SCV000030233	risk factor	Melanoma, cutaneous malignant, susceptibility to, 2	1994-04-15	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429694	SCV000505095	likely pathogenic	Melanoma	2015-07-14	no assertion criteria provided	literature only
Institute of Medical Sciences, Banaras Hindu University	RCV001255666	SCV001432231	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research