ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1601G>T (p.Arg534Leu)

dbSNP: rs587778523
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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 RCV000567489 SCV000662214 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-12 criteria provided, single submitter clinical testing The p.R534L variant (also known as c.1601G>T), located in coding exon 10 of the MSH2 gene, results from a G to T substitution at nucleotide position 1601. The arginine at codon 534 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified once in a cohort of 133 breast cancer patients (Lin PH et al. Oncotarget, 2016 Feb;7:8310-20). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000567489 SCV000684954 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-24 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 534 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 has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in one individual each affected with early onset colorectal cancer (PMID: 32973888) and early onset breast cancer (PMID: 26824983). This variant has been identified in 4/251348 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.
Counsyl RCV000662462 SCV000784943 uncertain significance Lynch syndrome 1 2017-02-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001039308 SCV001202833 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-11-17 criteria provided, single submitter clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153734 SCV003843718 likely pathogenic Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662462 SCV004018235 uncertain significance Lynch syndrome 1 2023-03-16 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health RCV004000846 SCV004833915 uncertain significance Lynch syndrome 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 534 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 has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in one individual each affected with early onset colorectal cancer (PMID: 32973888) and early onset breast cancer (PMID: 26824983). This variant has been identified in 4/251348 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.

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