ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7472T>A (p.Met2491Lys)

dbSNP: rs369075403
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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 RCV000580264 SCV000681868 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-19 criteria provided, single submitter clinical testing This missense variant replaces methionine with lysine at codon 2491 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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 not been identified 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 RCV004562538 SCV000960947 uncertain significance Familial adenomatous polyposis 1 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 2491 of the APC protein (p.Met2491Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 489495). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000580264 SCV004088705 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-27 criteria provided, single submitter clinical testing The p.M2491K variant (also known as c.7472T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 7472. The methionine at codon 2491 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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