Submissions for variant NM_000251.3(MSH2):c.1130A>G (p.Gln377Arg)

gnomAD frequency: 0.00001  dbSNP: rs776174711

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229489	SCV000284092	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000479748	SCV000570113	uncertain significance	not provided	2017-08-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1130A>G at the cDNA level, p.Gln377Arg (Q377R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln377Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln377Arg occurs at a position that is conserved across species and is located in the Lever domain (L?tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gln377Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000662583	SCV000785206	uncertain significance	Lynch syndrome 1	2017-06-02	criteria provided, single submitter	clinical testing
Mendelics	RCV003491996	SCV001135723	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017396	SCV001178472	likely benign	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001017396	SCV001351475	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 377 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193852	SCV001363000	uncertain significance	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1130A>G (p.Gln377Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1130A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001193852	SCV002065200	uncertain significance	not specified	2021-03-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1130A>G, in exon 7 that results in an amino acid change, p.Gln377Arg. This sequence change has been described in gnomAD with a frequency of 0.0029% in the Latino sub-population (dbSNP rs776174711). The p.Gln377Arg change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln377Arg substitution. This sequence change does not appear to have been previously described in patients with MSH2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Gln377Arg change remains unknown at this time.
Myriad Genetics, Inc.	RCV000662583	SCV004018222	uncertain significance	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662583	SCV004193912	uncertain significance	Lynch syndrome 1	2023-10-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998751	SCV004827143	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 377 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that cells expressing this variant responded normally to the anti-metabolite 6-thioguanine (PMID: 33357406). This variant has been reported in an individual suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 chromosomes 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.