Submissions for variant NM_000251.3(MSH2):c.1898T>C (p.Ile633Thr)

gnomAD frequency: 0.00001  dbSNP: rs864622093

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206123	SCV000259316	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000519579	SCV000616939	uncertain significance	not provided	2017-05-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1898T>C at the cDNA level, p.Ile633Thr (I633T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in an HPV-positive head and neck squamous cell carcinoma (Lechner 2013). MSH2 Ile633Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile633Thr occurs at a position that is not conserved and is located within the ATPase domain and the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Ile633Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000562458	SCV000673870	likely benign	Hereditary cancer-predisposing syndrome	2018-03-29	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	RCV000562458	SCV000690027	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 633 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). 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 1/251470 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	RCV001201177	SCV001372232	uncertain significance	not specified	2020-06-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1898T>C (p.Ile633Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain 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 4e-06 in 251470 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.1898T>C 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 (VUS n=3, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997560	SCV004829829	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 633 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). 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 1/251470 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.
GenomeConnect, ClinGen	RCV000519579	SCV002075157	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-02-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.