Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076610 | SCV000107646 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV000492044 | SCV000580473 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-03-29 | criteria provided, single submitter | clinical testing | The p.V163D variant (also known as c.488T>A), located in coding exon 3 of the MSH2 gene, results from a T to A substitution at nucleotide position 488. The valine at codon 163 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported in individuals meeting Amsterdam I and/or II criteria whose tumors exhibited high microsatellite instability and/or loss of MSH2 on immunohistochemistry (Ward, R et al. J Cancer Res Clin Oncol. 2002 Aug;128(8):403-11; Rhees, J et al. Fam Cancer. 2014 Jun;13(2):219-25; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Color Diagnostics, |
RCV000492044 | SCV000690112 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-09-01 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with aspartic acid at codon 163 in the DNA binding domain of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant impairs DNA mismatch repair activity (MMR) (PMID: 26951660, 30504929). This variant has been reported in two individuals affected with Lynch syndrome (PMID: 12200596, 17192056, 18383312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Invitae | RCV003593902 | SCV004292475 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-07-20 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Val163 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 29212164), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 91107). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12200596, 24114314; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 163 of the MSH2 protein (p.Val163Asp). |