Submissions for variant NM_000251.3(MSH2):c.1808A>T (p.Asp603Val)

dbSNP: rs267607985

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562065	SCV000664854	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	The p.D603V pathogenic mutation (also known as c.1808A>T), located in coding exon 12 of the MSH2 gene, results from an A to T substitution at nucleotide position 1808. The aspartic acid at codon 603 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been identified in individuals whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or loss of both MSH2/MSH6 expression by immunohistochemistry (IHC) (Ambry internal data; Sekine R et al. Jpn J Clin Oncol, 2022 Jan;52:81-85). This variant was also identified in conjunction with a truncating MSH2 variant (p.D680*) in a tumor sample taken from a cancer of unknown primary that was MSI-H by NGS and had loss of both MSH2/MSH6 expression by IHC (Gatalica Z et al. Eur J Cancer, 2018 05;94:179-186). In another study, this variant segregated with disease in a family that met Amsterdam II criteria for Lynch syndrome (Sekine R et al. Jpn J Clin Oncol, 2022 Jan;52:81-85). 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). Reduced mismatch repair function and protein stability were demonstrated in another study that used CRISPR-Cas9 gene editing to introduce MSH2 missense variants in human embryonic stem cells (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349666	SCV001544021	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-02-01	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Asp603 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18186571, 30504929, 33357406). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31237724). Experimental studies have shown that this missense change affects MSH2 function (PMID: 31237724, 33357406). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 480909). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 603 of the MSH2 protein (p.Asp603Val).
GeneDx	RCV003317285	SCV004021909	likely pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein stability, impaired MMR function, and response to DNA damaging agents similar to other known pathogenic variant(s) (Rath et al., 2019; Jia et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29571084, 36484308, 33357406, 9774676, 18822302, 21120944, 34761252, 31237724)
Color Diagnostics, LLC DBA Color Health	RCV000562065	SCV001346983	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-13	flagged submission	clinical testing	This missense variant replaces aspartic acid with valine at codon 603 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant abrogates mismatch repair‐dependent damage response (PMID: 31237724). This variant has been reported in an individual affected with unspecified cancer type, who also carried a pathogenic truncation variant in the same gene (PMID: 29571084). To our knowledge, this variant has not been reported in individuals diagnosed with Lynch syndrome in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.