Submissions for variant NM_000179.3(MSH6):c.2281A>G (p.Arg761Gly)

gnomAD frequency: 0.00008  dbSNP: rs199876321

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129031	SCV000172939	likely benign	Hereditary cancer-predisposing syndrome	2021-04-06	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	RCV000195792	SCV000254294	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000657020	SCV000279316	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal, breast, and other cancers (Rey et al., 2017; Ricker et al., 2017; Martin-Morales et al., 2018; Yehia et al., 2018; Castillo-Guardiola et al., 2022); This variant is associated with the following publications: (PMID: 23621914, 28502729, 28640387, 30256826, 29684080, 26635394, Alshathly2021[article], 35245693, 17531815, 21120944, 35089076, 33471991)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657020	SCV000601528	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 30256826 (2018), 28640387 (2017)), breast cancer (PMID: 35245693 (2022)), and melanoma (PMID: 29684080 (2018)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00038 (13/34586 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000129031	SCV000685275	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 761 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals with personal and/or family history of Lynch syndrome-associated cancer and/or polyps (PMID: 28502729, 30256826), colorectal cancer who also had a pathogenic MUTYH variant (PMID: 28640387), skin melanoma (PMID: 29684080), breast cancer (PMID: 35245693), or lymphoblastic leukemia (DOI: 10.5603/oJ.2021.0046). In a large breast cancer case-control study, this variant was reported in 7/60466 cases and 7/53461 unaffected controls (PMID: 33471991). This variant has been identified in 15/251138 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	RCV000662484	SCV000784983	uncertain significance	Lynch syndrome 5	2017-03-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002443	SCV001160383	uncertain significance	not specified	2019-03-26	criteria provided, single submitter	clinical testing	The MSH6 c.2281A>G; p.Arg761Gly variant (rs199876321) is reported in two probands who underwent hereditary colorectal cancer testing (Rey 2017). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 140836). It is found in the general population with an overall allele frequency of 0.006% (15/251138 alleles) Genome Aggregation Database. The arginine at codon 761 is moderately conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Rey JM et al. Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing. J Mol Diagn. 2017 Jul;19(4):589-601.
Illumina Laboratory Services, Illumina	RCV000662484	SCV001300702	uncertain significance	Lynch syndrome 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002443	SCV001338334	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2281A>G (p.Arg761Gly) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 (i.e., 15 heterozygotes) in 251138 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. On the other hand, the variant, c.2281A>G, has also been reported in the literature in individuals affected with polyps and/or tumors belonging to Lynch syndrome tumor spectrum (e.g. Rey_2017, Ricker_2017, Martin-Morales_2018), and in individuals affected with other tumor phenotypes (e.g. Yehia_2018, Dorling_2021, Castillo-Guardioloa_2022, Sahin_2022 (No PMID)), but was also found in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23621914, 28502729, 28640387, 30256826, 29684080, 33471991, 35245693, 35089076). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=7) and Likely Benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000129031	SCV002535716	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000662484	SCV004015202	uncertain significance	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing	MSH6 c.2281A>G (p.Arg761Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00006 in 251138 control chromosomes (gnomAD). c.2281A>G has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer and melanoma (e.g. Martin-Morales_2018, Rey_2017, Ricker_2017, Yehia_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662484	SCV004019000	likely benign	Lynch syndrome 5	2023-03-29	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	RCV003460882	SCV004197749	uncertain significance	Endometrial carcinoma	2023-09-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001002443	SCV004243093	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997472	SCV004841950	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 761 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals with personal and/or family history of Lynch syndrome-associated cancer and/or polyps (PMID: 28502729, 30256826), colorectal cancer who also had a pathogenic MUTYH variant (PMID: 28640387), skin melanoma (PMID: 29684080), breast cancer (PMID: 35245693), or lymphoblastic leukemia (DOI: 10.5603/oJ.2021.0046). In a large breast cancer case-control study, this variant was reported in 7/60466 cases and 7/53461 unaffected controls (PMID: 33471991). This variant has been identified in 15/251138 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.