ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.11C>G (p.Ala4Gly)

gnomAD frequency: 0.00001  dbSNP: rs1277299943
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000772904 SCV000906286 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 4 of the CDKN2A (p16INK4A) protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/224328 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000804694 SCV000944615 uncertain significance Familial melanoma 2024-06-08 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 alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4 of the CDKN2A (p16INK4a) protein (p.Ala4Gly). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 628437). 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 tolerated. 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 RCV000772904 SCV002645084 likely benign Hereditary cancer-predisposing syndrome 2024-10-09 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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