Submissions for variant NM_000077.5(CDKN2A):c.151G>A (p.Val51Ile)

gnomAD frequency: 0.00002  dbSNP: rs762630679

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531849	SCV000637395	uncertain significance	Familial melanoma	2025-01-07	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. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 51 of the CDKN2A (p16INK4a) protein (p.Val51Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.194G>A (p.Gly65Asp) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 463485). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000773208	SCV000906793	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 51 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/220322 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000773208	SCV001172354	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.V51I variant (also known as c.151G>A) is located in coding exon 2 of the CDKN2A gene. The valine at codon 51 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 2. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193450	SCV001362281	uncertain significance	not specified	2019-02-27	criteria provided, single submitter	clinical testing	Variant summary: The CDKN2A gene encodes multiple alternative transcripts, coding for different proteins; the most well-studied are the p16 (INK4A) and the p14 (ARF) proteins. In p16 (INK4A) the variant results in c.151G>A (p.Val51Ile), causing a conservative amino acid change located in the Ankyrin repeat-containing domain with four of five in-silico tools predict a damaging effect of the variant on protein function. Alternatively, in p14 (ARF) this nucleotide change results in the formation of c.194G>A (p.Gly65Asp). An in silico study predicted that the variant has a benign effect for p16 and is possibly damaging for ARF (Yang 2005). In addition, this variant is located at the first 5' position in exon 2: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-06 in 220322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.151G>A has been reported in the literature as a somatic variant in various tumors (e.g. Ohta 1996, COSMIC database, Jauhri_2016). However, these report(s) do not provide unequivocal conclusions about association of the germline variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant had no damaging effect on the mouse homologue of the p16 protein (i.e. it had similar function to the WT), however, authors did not test the effect of the variant on the other affected protein, p19 ARF (the mouse homologue of p14 ARF) (Zhang 2001). Therefore these data do not allow convincing conclusions about the variant effect. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193450	SCV005090826	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing