ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3631A>G (p.Met1211Val)

dbSNP: rs780084585
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003742687 SCV000647462 uncertain significance Familial adenomatous polyposis 1 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1211 of the APC protein (p.Met1211Val). This variant is present in population databases (rs780084585, gnomAD 0.003%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 20434453). ClinVar contains an entry for this variant (Variation ID: 469931). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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 RCV000563324 SCV000672580 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-04 criteria provided, single submitter clinical testing The p.M1211V variant (also known as c.3631A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3631. The methionine at codon 1211 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was reported in a family with an attenuated FAP phenotype, however clinical details were limited (Castellsagué E et al. Gastroenterology, 2010 Aug;139:439-47, 447.e1). This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health RCV000563324 SCV001345148 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-01 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 1211 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 been reported in an individual affected with an attenuated form of familial adenomatous polyposis (PMID: 20434453). This variant has been identified in 1/250614 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.
All of Us Research Program, National Institutes of Health RCV003999384 SCV004837817 uncertain significance Classic or attenuated familial adenomatous polyposis 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 1211 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 been reported in an individual affected with an attenuated form of familial adenomatous polyposis (PMID: 20434453). This variant has been identified in 1/250614 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.

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