Submissions for variant NM_000251.3(MSH2):c.2072T>C (p.Ile691Thr)

dbSNP: rs754824872

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195748	SCV000254400	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-10	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 691 of the MSH2 protein (p.Ile691Thr). This variant is present in population databases (rs754824872, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer (PMID: 11606497, 21671081). ClinVar contains an entry for this variant (Variation ID: 216349). 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 with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000579733	SCV000685007	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 691 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). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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.
Sema4, Sema4	RCV000579733	SCV002534444	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
GeneDx	RCV002307442	SCV002601231	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history of colorectal cancer, with at least some tumors demonstrating microsatellite instability and/or loss of MSH2 protein expression, but all of whom also harbored a second MSH2 variant (Samowitz et al., 2001; Kovac et al., 2011; Zhunussova et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31428572, 11606497, 21671081, 18822302, 21120944)
Ambry Genetics	RCV000579733	SCV002726347	likely benign	Hereditary cancer-predisposing syndrome	2021-10-28	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	RCV003997018	SCV004825283	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 691 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). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21671081) and colorectal cancer (PMID: 11606497, 31428572). This variant has been identified in 1/251474 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.