Submissions for variant NM_000179.3(MSH6):c.3104G>A (p.Arg1035Gln)

dbSNP: rs730881801

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196222	SCV000254303	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000759859	SCV000567271	uncertain significance	not provided	2019-11-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with prostate cancer and in the tumor of an individual with microsatellite unstable colon cancer who also carried an MSH2 pathogenic variant (Lu 2015, Hampel 2018); This variant is associated with the following publications: (PMID: 26689913, 27978560, 29596542)
Ambry Genetics	RCV000568269	SCV000676117	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.R1035Q variant (also known as c.3104G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 3104. The arginine at codon 1035 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a prostate cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759859	SCV000889481	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000044 (5/112482 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35402282 (2022), 35127508 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000568269	SCV000906514	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1035 of the MSH6 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 26689913). In a large breast cancer case-control study, this variant has been reported in 3/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has been identified in 7/248120 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.
Sema4, Sema4	RCV000568269	SCV002535792	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272172	SCV002556658	uncertain significance	Lynch syndrome 5	2021-06-24	criteria provided, single submitter	clinical testing	The MSH6 c.3104G>A variant is classified as VUS (PP3), and was detected with another somatic pathogenic MSH6 variant.
Myriad Genetics, Inc.	RCV002272172	SCV004019224	likely benign	Lynch syndrome 5	2023-03-31	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320595	SCV004024797	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997000	SCV004837146	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1035 of the MSH6 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 26689913). In a large breast cancer case-control study, this variant has been reported in 3/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has been identified in 7/248120 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.