ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1021C>G (p.Leu341Val)

gnomAD frequency: 0.00004  dbSNP: rs748115066
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220354 SCV000276256 likely benign Hereditary cancer-predisposing syndrome 2023-03-21 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.
Invitae RCV000232111 SCV000284087 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000236110 SCV000293975 uncertain significance not provided 2023-09-07 criteria provided, single submitter clinical testing Observed in an individual with colorectal cancer whose tumor demonstrated microsatellite instability and loss of MSH2/MSH6 expression, as well as in individuals with endometrial, breast cancer, or osteosarcoma (Rodrguez-Soler et al., 2013; Yehia et al., 2018; Mirabello et al., 2020; Bhai et al., 2021); Published functional studies demonstrate mismatch repair function similar to wildtype (Jia et al., 2020); 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: 23354017, 22144684, 29684080, 26344056, 18822302, 21120944, 32191290, 34326862, 32522261, 33357406)
Counsyl RCV000662429 SCV000784883 uncertain significance Lynch syndrome 1 2017-01-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000220354 SCV000908289 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-26 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 341 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 an individual affected with colorectal cancer that exhibited loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 23354017). This variant has been identified in 7/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1022T>C (p.Leu341Pro), is considered to be disease-causing (ClinVar variation ID: 234622), suggesting that this position is important for the protein function. 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.
Myriad Genetics, Inc. RCV000662429 SCV004043995 likely benign Lynch syndrome 1 2023-05-08 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics RCV000662429 SCV004196837 uncertain significance Lynch syndrome 1 2023-05-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997950 SCV004824554 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 341 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 not been reported in an individual affected with colorectal cancer that exhibited loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 23354017). This variant has been identified in 7/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1022T>C (p.Leu341Pro), is considered to be disease-causing (ClinVar variation ID: 234622), suggesting that this position is important for the protein function. 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.

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