Submissions for variant NM_000251.3(MSH2):c.1807G>C (p.Asp603His)

dbSNP: rs63750657

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485623	SCV000565197	uncertain significance	not provided	2018-02-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1807G>C at the cDNA level, p.Asp603His (D603H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp603His was not observed in large population cohorts (Lek 2016). This variant is located in regions of interaction with MSH6, MSH3 and EXO1 as well as in the Lever Domain (Kansikas 2011, L?tzen 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Asp603His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001187838	SCV001354726	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine 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. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
Ambry Genetics	RCV001187838	SCV002713992	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The p.D603H variant (also known as c.1807G>C), located in coding exon 12 of the MSH2 gene, results from a G to C substitution at nucleotide position 1807. The aspartic acid at codon 603 is replaced by histidine, an amino acid with similar properties. 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). Based on internal structural analysis, p.D603H is anticipated to result in a significant decrease in structural stability (Gupta S et al. Nat. Struct. Mol. Biol., 2011 Dec;19:72-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). 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.
Myriad Genetics, Inc.	RCV002280119	SCV004186590	likely pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 33357406].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003758780	SCV004485470	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-15	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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 418316). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 603 of the MSH2 protein (p.Asp603His).
University of Washington Department of Laboratory Medicine, University of Washington	RCV002280119	SCV002568349	likely pathogenic	Lynch syndrome 1	2018-07-13	no assertion criteria provided	clinical testing	This is the same MSH2 variant that was reportedly detected in two additional affected family members of the patient. Family cosegregation analysis was performed using Analyze.MyVariant.org, which gave a likelihood ratio of 6.7:1 in favor of pathogenicity. IHC in one of the relatives tumors showed loss of MSH2 and partial loss of MSH6 staining. This variant occurs at a position that is evolutionary conserved. This variant is not reported in population databases (gnomad.broadinstitute.org) or in the InSiGHT database. This combined evidence all suggests that the MSH2 p.D603H variant is likely to cause Lynch syndrome in this family.