Submissions for variant NM_000251.3(MSH2):c.1601G>A (p.Arg534His)

gnomAD frequency: 0.00004  dbSNP: rs587778523

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656878	SCV000149413	uncertain significance	not provided	2025-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mismatch repair function similar to wildtype (PMID: 33357406); Observed in an individual with colorectal cancer whose tumor showed normal immunohistochemistry results and had microsatellite stability (PMID: 25142776); This variant is associated with the following publications: (PMID: 24728327, 28494185, 18822302, 9774676, 21120944, 26824983, 33471991, 31396961, 34326862, 29684080, 33357406, 25142776)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122981	SCV000166264	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492001	SCV000580410	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-12	criteria provided, single submitter	clinical testing	The p.R534H variant (also known as c.1601G>A), located in coding exon 10 of the MSH2 gene, results from a G to A substitution at nucleotide position 1601. The arginine at codon 534 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a 68-year-old male patient with colorectal cancer; however this individuals tumor exhibited normal IHC and was MSS (Kraus C et al. Int J Cancer, 2015 Mar;136:E559-68). Another study reported this alteration in a cohort of Chinese esophageal squamous cell carcinoma patients (Ko JM et al. Int J Cancer, 2020 02;146:1042-1051). This variant was reported in 7/60,466 breast cancer cases but also reported in 6/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000492001	SCV000684953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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 individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 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	RCV000662395	SCV000784809	uncertain significance	Lynch syndrome 1	2016-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121559	SCV000917715	uncertain significance	not specified	2018-07-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1601G>A (p.Arg534His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp domain (IPR007861), which is inserted between the two subdomains of the core domain. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246194 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.3e-05 vs 0.00057), allowing no conclusion about variant significance. c.1601G>A has been reported in the literature in individuals affected with colorectal cancer and in an individual with a positive family history of inherited cancer disorder (Kraus_2015, O'Leary_2014). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.998G>A, p.Cys333Tyr (LOVD)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656878	SCV002046197	uncertain significance	not provided	2024-06-07	criteria provided, single submitter	clinical testing	The MSH2 c.1601G>A (p.Arg534His) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 25142776 (2015), 28494185 (2017)), breast cancer (34326862 (2021), 33471991 (2021), see LOVD (https://databases.lovd.nl/shared/)), and esophageal cancer (PMID: 31396961 (2020)). This variant has also been observed in reportedly healthy individuals (PMIDs: 23012121 (2012), 24728327 (2014), 33471991 (2021), see LOVD (https://databases.lovd.nl/shared/)). A cell-survival screening assay suggests this variant has neutral effects on DNA mismatch repair function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000098 (3/30606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000492001	SCV002534382	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662395	SCV004018328	likely benign	Lynch syndrome 1	2024-12-10	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: 27363726].
Baylor Genetics	RCV000662395	SCV004196193	uncertain significance	Lynch syndrome 1	2023-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997272	SCV004833904	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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 individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394385	SCV006056433	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2024-06-24	criteria provided, single submitter	clinical testing
ITMI	RCV000121559	SCV000085753	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000492001	SCV000788030	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734649	SCV005365883	uncertain significance	MSH2-related disorder	2024-04-14	no assertion criteria provided	clinical testing	The MSH2 c.1601G>A variant is predicted to result in the amino acid substitution p.Arg534His. This variant has been reported in individuals with colorectal cancer (Kraus et al. 2015. PubMed ID: 25142776; Yehia et al. 2018. PubMed ID: 29684080), breast cancer (Bhai et al. 2021. PubMed ID: 34326862), and esophageal cancer (Ko et al. 2019. PubMed ID: 31396961). However, this variant was present at similar frequencies in a large cohort of breast cancer patients (n = 7; 0.12%) compared to unaffected controls (n = 6; 0.011%) (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991) and was classified as "functionally neutral" based on the results of a high-throughput DNA damage repair assay (Jia et al. 2021. PubMed ID: 33357406). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and is classified as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127632/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.