Submissions for variant NM_000251.3(MSH2):c.2321T>C (p.Ile774Thr)

dbSNP: rs878853811

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473566	SCV000548241	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 774 of the MSH2 protein (p.Ile774Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408514). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761089	SCV000891004	uncertain significance	Lynch syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The MSH2 c.2321T>C (p.Ile774Thr) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Six of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), however these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
Ambry Genetics	RCV001015184	SCV001175993	likely benign	Hereditary cancer-predisposing syndrome	2022-08-30	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	RCV001015184	SCV001339564	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This variant is located in 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 not been identified 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	RCV001284505	SCV001470338	uncertain significance	not provided	2020-05-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001284505	SCV001992607	uncertain significance	not provided	2019-04-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30309722)
Sema4, Sema4	RCV001015184	SCV002534468	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315429	SCV004015211	uncertain significance	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing	The p.I774T variant (also known as c.2321T>C), located in coding exon 14 of the MSH2 gene, results from a T to C substitution at nucleotide position 2321. The isoleucine at codon 774 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This variant was not found in gnomAD exomes. There is a ClinVar entry (408514) for this variant with 4 submissions, all of which list it as uncertain significance. In addition, the in-silico prediction for this alteration showed pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL and 6 more vs 2 benign predictions from MutationAssessor and PrimateAI. Alternative variant chr2:47705520 A⇒G (Ile774Val) is classified Likely Pathogenic
All of Us Research Program, National Institutes of Health	RCV000761089	SCV004825880	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This variant is located in 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 not been identified 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.