Submissions for variant NM_000179.3(MSH6):c.1081C>T (p.Arg361Cys)

gnomAD frequency: 0.00012  dbSNP: rs587782651

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132064	SCV000187127	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	The p.R361C variant (also known as c.1081C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1081. The arginine at codon 361 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000230863	SCV000283700	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132064	SCV000690171	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 13/251080 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420719	SCV000695774	uncertain significance	not specified	2021-04-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1081C>T (p.Arg361Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251080 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00014), allowing no conclusion about variant significance. c.1081C>T has been reported in the literature in individuals affected with prostate cancer or other type of cancer (Rodrigues_2018, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758606	SCV000887360	likely benign	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.1081C>T has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589862	SCV000889453	uncertain significance	not provided	2017-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000589862	SCV001812752	likely benign	not provided	2019-02-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24983367, 26900293)
All of Us Research Program, National Institutes of Health	RCV000758606	SCV004837669	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/251080 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	RCV000758606	SCV001551706	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Arg361Cys variant was not identified in the literature nor was it identified in the COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587782651) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x found in prostate tissue). The variant was identified in control databases in 13 of 245822 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5478 chromosomes (freq: 0.0002), Latino in 11 of 33560 chromosomes (freq: 0.0003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); it was not observed in the African, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg361 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.