Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002045182 | SCV002291071 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 609 of the MSH2 protein (p.Ala609Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer, extramammary Paget disease, and/or suspicion of Lynch syndrome (PMID: 15849733, 27487738, 32914570). ClinVar contains an entry for this variant (Variation ID: 1502496). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive 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 | RCV002407274 | SCV002711111 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-03 | criteria provided, single submitter | clinical testing | The p.A609V variant (also known as c.1826C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1826. The alanine at codon 609 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In a study of 1,721 German probands suspected of HNPCC, this mutation (designated as p.Ala609Val) was detected in one family (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This variant was also reported as germline in a male patient with extramammary Paget disease diagnosed at 75; the tumor was MSI-L and demonstrated normal MSH2 expression by IHC (Kang Z et al. Am. J. Surg. Pathol. 2016 11;40:1517-1525). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |