Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000759834 | SCV000566957 | uncertain significance | not provided | 2018-10-26 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.422T>C at the cDNA level, p.Met141Thr (M141T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Met141Thr was observed at an allele frequency of 0.01% (2/17248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Met141Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759834 | SCV000889439 | uncertain significance | not provided | 2017-11-17 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000773079 | SCV000906513 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-05 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with threonine at codon 141 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 2/251414 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. |
Invitae | RCV001246708 | SCV001420084 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-07-29 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000773079 | SCV002632799 | likely benign | Hereditary cancer-predisposing syndrome | 2023-05-22 | 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. |
Baylor Genetics | RCV003470539 | SCV004196827 | uncertain significance | Lynch syndrome 1 | 2023-05-25 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004002296 | SCV004830221 | uncertain significance | Lynch syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with threonine at codon 141 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 2/251414 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. |