Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001014562 | SCV001175285 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | The p.R711P variant (also known as c.2132G>C), located in coding exon 13 of the MSH2 gene, results from a G to C substitution at nucleotide position 2132. The arginine at codon 711 is replaced by proline, an amino acid with dissimilar properties. This variant was reported in an individual diagnosed with colorectal cancer at age 49, who also had a family history of colorectal and other Lynch syndrome-associated cancers (Thodi G et al. BMC Cancer, 2010 Oct;10:544). In addition, this variant was identified in a proband whose endometrial tumor demonstrated high microsatellite instability with normal mismatch repair protein expression by immunohistochemistry (Hampel H et al. Gynecol Oncol, 2021 Jan;160:161-168). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001036842 | SCV001200225 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 711 of the MSH2 protein (p.Arg711Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20937110; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 820781). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003455086 | SCV004186645 | likely pathogenic | Lynch syndrome 1 | 2023-08-07 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. |