Submissions for variant NM_000251.3(MSH2):c.2786G>A (p.Arg929Gln)

gnomAD frequency: 0.00002  dbSNP: rs587779967

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759829	SCV000149430	uncertain significance	not provided	2015-06-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2786G>A at the cDNA level, p.Arg929Gln (R929Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). It has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism, to our knowledge. However, the MSH2 Arg929Gln amino acid substitution has previously been reported as a somatic change in one endometrial tumor according to the Catalogue of Somatic Mutations in Cancer (COSMIC). MSH2 Arg929Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Arg929Gln occurs at a position that is not conserved and is located within the region of interaction with MSH6 and MSH3 (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Arg929Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000469769	SCV000548126	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583830	SCV000690097	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 929 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 4/248546 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.
Counsyl	RCV000662933	SCV000785889	uncertain significance	Lynch syndrome 1	2018-01-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759829	SCV000889431	uncertain significance	not provided	2019-02-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000583830	SCV001177570	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-24	criteria provided, single submitter	clinical testing	The p.R929Q variant (also known as c.2786G>A), located in coding exon 16 of the MSH2 gene, results from a G to A substitution at nucleotide position 2786. The arginine at codon 929 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759829	SCV001471754	uncertain significance	not provided	2020-02-27	criteria provided, single submitter	clinical testing	The MSH2 c.2786G>A; p.Arg929Gln variant (rs587779967), to our knowledge, is not reported in the medical literature but is reported in the ClinVar database (Variation ID: 127639). This variant is found in the general population with a low overall allele frequency of 0.002% (4/248546 alleles) in the Genome Aggregation Database. The arginine at codon 929 is moderately conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time.
Myriad Genetics, Inc.	RCV000662933	SCV004018342	likely benign	Lynch syndrome 1	2023-03-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997275	SCV004829975	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 929 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 4/248546 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.