ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2006G>T (p.Gly669Val)

dbSNP: rs63751640
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076356 SCV000107382 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (full inactivation of variant allele)
Ambry Genetics RCV000491447 SCV000580412 pathogenic Hereditary cancer-predisposing syndrome 2021-05-10 criteria provided, single submitter clinical testing The p.G669V pathogenic mutation (also known as c.2006G>T) is located in coding exon 13 of the MSH2 gene. The glycine at codon 669 is replaced by valine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 13 and has been confirmed to cause skipping of exon 13 (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Tricarico R et al. Hum Mutat. 2017 01;38:64-77). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data). 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.
Invitae RCV000692084 SCV000819891 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 669 of the MSH2 protein (p.Gly669Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 10612827, 21520333, 27629256; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90854). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 27629256, 28422960). Studies have shown that this missense change results in partial or complete exclusion of exon 13 and introduces a premature termination codon (PMID: 26247049, 27629256). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002477219 SCV002774359 pathogenic not provided 2021-08-17 criteria provided, single submitter clinical testing This variant has been reported to segregate with disease in families with Lynch syndrome (PMID: 27629256 (2017), and the UMD database (http://www.umd.be/)). In addition, experimental studies indicate that the variant causes an out-of-frame skipping of exon 13 in the MSH2 mRNA, and has deleterious effects on DNA mismatch repair activity in vitro (PMIDs: 27629256 (2017) and 26247049 (2015)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc. RCV003452879 SCV004186732 likely pathogenic Lynch syndrome 1 2023-08-07 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, 27629256]. Functional studies indicate this variant impacts protein function [PMID: 27629256]. This variant is expected to disrupt protein structure [Myriad internal data].
Mayo Clinic Laboratories, Mayo Clinic RCV000581599 SCV000691909 uncertain significance not specified no assertion criteria provided clinical testing

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