ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2296A>G (p.Ile766Val)

gnomAD frequency: 0.00001  dbSNP: rs374399939
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165690 SCV000216428 likely benign Hereditary cancer-predisposing syndrome 2023-01-06 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.
GeneDx RCV000766654 SCV000293211 uncertain significance not provided 2017-05-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2296A>G at the cDNA level, p.Ile766Val (I766V) 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 being pathogenic or benign. MSH2 Ile766Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile766Val occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile766Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000165690 SCV000690061 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-30 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 766 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). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/251442 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000798203 SCV000937805 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-10-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462184 SCV004196311 uncertain significance Lynch syndrome 1 2023-08-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004806138 SCV005429154 uncertain significance Lynch syndrome 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 766 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). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/251442 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000202197 SCV000257174 uncertain significance not specified no assertion criteria provided research

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