Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000219613 | SCV000274152 | likely benign | Hereditary cancer-predisposing syndrome | 2019-02-22 | 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. |
Gene |
RCV000483517 | SCV000567758 | uncertain significance | not provided | 2018-04-06 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.1489A>G at the cDNA level, p.Ile497Val (I497V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile497Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Clamp domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may create a cryptic splice donor site upstream of the natural splice donor, leading to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH2 Ile497Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Labcorp Genetics |
RCV000630079 | SCV000751035 | benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-19 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000219613 | SCV000908304 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-17 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 497 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 2/251298 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000483517 | SCV001134339 | uncertain significance | not provided | 2018-11-02 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000986672 | SCV001135732 | uncertain significance | Lynch syndrome 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002229222 | SCV002511448 | uncertain significance | not specified | 2023-12-21 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.1489A>G (p.Ile497Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1489A>G has been reported in the literature as a VUS in a report that aimed at assessing the prevalence of secondary findings in 19 NCCN designated genes within a cohort of 400 individuals without a cancer diagnosis undergoing whole exome sequencing (WES) analysis (example, Kraemer_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31422574). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. |
All of Us Research Program, |
RCV003997850 | SCV004833463 | uncertain significance | Lynch syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 497 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 2/251298 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. |