Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003765322 | SCV000259839 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2404 of the APC protein (p.Met2404Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 219778). 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 | RCV002372197 | SCV002673455 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-10-08 | criteria provided, single submitter | clinical testing | The p.M2404K variant (also known as c.7211T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 7211. The methionine at codon 2404 is replaced by lysine, an amino acid with similar properties. This alteration, classified as a variant of unknown significance by study authors, has been reported in a patient with a personal history of breast cancer diagnosed at age 38 and family history of stomach and breast cancer (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660). This amino acid position is not well 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509301 | SCV002819642 | uncertain significance | not specified | 2022-12-19 | criteria provided, single submitter | clinical testing | Variant summary: APC c.7211T>A (p.Met2404Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7211T>A has been reported in the literature in individuals affected with Breast Cancer (Chan_2018) without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |