Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076034 | SCV000107048 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Invitae | RCV001230748 | SCV001403238 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 18781619). ClinVar contains an entry for this variant (Variation ID: 90539). This missense change has been observed in individuals with Lynch syndrome (PMID: 11870161, 17165155, 18781619). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 359 of the MSH2 protein (p.Arg359Ser). |
| Ambry Genetics | RCV002415553 | SCV002727573 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-11 | criteria provided, single submitter | clinical testing | The p.R359S pathogenic mutation (also known as c.1077A>T) is located in coding exon 7 of the MSH2 gene. The arginine at codon 359 is replaced by serine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 7. This variant has been reported in four affected relatives in a family meeting Amsterdam criteria; their tumors were MSI-H and showed loss of MSH2 protein on immunohistochemistry (Bianchi F et al. Fam Cancer, 2007;6:97-102). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). Additional functional studies have shown this mutation to result in abnormal subcellular localization patterns and reduced MMR efficiency compared to the wild type (Gammie AE et al. Genetics, 2007 Oct;177:707-21; Belvederesi L et al. Hum Mutat, 2008 Nov;29:E296-309). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |