ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8425G>A (p.Val2809Met)

dbSNP: rs886059801
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000340442 SCV000452058 uncertain significance APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV003743701 SCV000647773 uncertain significance Familial adenomatous polyposis 1 2022-12-13 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2809 of the APC protein (p.Val2809Met). 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. 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. ClinVar contains an entry for this variant (Variation ID: 350425). This missense change has been observed in individual(s) with endometrial cancer and colorectal cancer (PMID: 29987844). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics RCV000575689 SCV000667298 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-03 criteria provided, single submitter clinical testing The p.V2809M variant (also known as c.8425G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 8425. The valine at codon 2809 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an individual diagnosed with endometrial cancer at age 30 and colon cancer at age 63, but without a personal history of colorectal polyposis (Kayser K et al. Int. J. Cancer, 2018 12;143:2800-2813). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000556737 SCV002073096 uncertain significance Familial adenomatous polyposis 1 criteria provided, single submitter clinical testing The missense variant p.V2809M in APC (NM_000038.6) has been reported before in two unrelated indviduals with endometrial as well as colon cancer but without a history of polyposis (Kayser K et al). It has been submitted to ClinVar as Uncertain significane. The p.V2809M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.V2809M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 2809 of APC is conserved in all mammalian species. The nucleotide c.8425 in APC is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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