Submissions for variant NM_000251.3(MSH2):c.62G>A (p.Arg21His)

dbSNP: rs730881760

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160594	SCV000211189	uncertain significance	not provided	2014-06-06	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.62G>A at the cDNA level, p.Arg21His (R21H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg21His 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 Histidine share similar properties, this is considered a conservative amino acid substitution. MSH2 Arg21His occurs at a position that is well conserved across mammals and is located in the mismatch binding domain (Lutzen 2008). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Arg21His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000539963	SCV000625445	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025106	SCV001187233	likely benign	Hereditary cancer-predisposing syndrome	2022-06-28	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.
All of Us Research Program, National Institutes of Health	RCV003998475	SCV004819734	uncertain significance	Lynch syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 21 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). 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 1/219676 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.