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

dbSNP: rs587778523

Total submissions: 7

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
Invitae	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.