Submissions for variant NM_000251.3(MSH2):c.164G>A (p.Arg55Gln)

gnomAD frequency: 0.00001  dbSNP: rs748196422

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000781988	SCV000920444	likely benign	Lynch syndrome	2018-12-19	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.05 (0.004)
Invitae	RCV000206288	SCV000260988	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214778	SCV000277643	likely benign	Hereditary cancer-predisposing syndrome	2022-04-26	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.
GeneDx	RCV000235898	SCV000292907	uncertain significance	not provided	2018-06-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.164G>A at the cDNA level, p.Arg55Gln (R55Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg55Gln 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 Arg55Gln occurs at a position where amino acids with properties similar to Arginine are are tolerated across species and is located in the mismatch binding domain (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 Arg55Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000214778	SCV000684958	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 55 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/233024 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235898	SCV002046265	uncertain significance	not provided	2020-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000781988	SCV004831927	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 55 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been reported in an individual affected with endometrial cancer with a family history of Lynch syndrome (www.umd.be). Other affected individuals from this family carried a variant in the MSH6 gene. This variant has been identified in 7/233024 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.