Submissions for variant NM_000179.3(MSH6):c.3284G>A (p.Arg1095His)

gnomAD frequency: 0.00003  dbSNP: rs63750253

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164048	SCV000214655	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	The p.R1095H variant (also known as c.3284G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3284. The arginine at codon 1095 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a proband diagnosed with metachronous MSI-H colorectal cancer (CRC) at 65y and 74y with a family history of CRC in 3 siblings diagnosed in their 60s and 70s (Kariola R et al. Hum Genet. 2003 Feb; 112(2):105-9). However, multiple functional assays have demonstrated that this alteration has activity comparable to wild type indicating it is likely not pathogenic (Kariola R et al. Hum. Genet. 2003 Feb;112(2):105-9; Ou J et al. Hum. Mutat. 2007 Nov;28(11):1047-54; Kansikas M et al. Hum. Mutat. 2011 Jan;32(1):107-15; Wielders EA et al. PLoS One. 2013 Sep 10;8(9):e74766; Kantelinen J et al. Hum. Mutat. 2012 Aug;33(8):1294-301). This variant was also identified once in a cohort comprised of 1231 colorectal cancer cases and 93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Based on internal structure analysis, p.R1095H strongly perturbs the structure of the ATPase domain more than a known likely pathogenic variant nearby (Warren JJ et al. Mol. Cell 2007 May;26:579-92). 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 conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524168	SCV000254312	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000412287	SCV000489603	uncertain significance	Lynch syndrome 5	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000985842	SCV000517286	likely benign	not provided	2021-04-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 23621914, 21120944, 17594722, 15354210, 22581703, 24040339, 12522549, 25980754, 25503501)
Color Diagnostics, LLC DBA Color Health	RCV000164048	SCV000685383	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1095 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). Functional studies have found this variant to be normal in in vitro mismatch DNA repair activity, complementation of MSH6-deficient mouse embryonic stem cells and MSH6 binding (PMID: 12522549, 22581703, 17594722, 24040339). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome associated cancer and/or polyps (PMID: 12522549, 25980754, 28944238) and with early-onset breast cancer (PMID: 25503501). This variant has been identified in 12/251448 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	RCV000433110	SCV000917734	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3284G>A (p.Arg1095His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. 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 4.8e-05 in 251448 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.3284G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals with colorectal cancer (e.g. Kariola_2013, Maxwell_2015, Wei_2016, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.4284dupT, p.Gln1429fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on mismatch repair (MMR) activity (e.g. Kantelinen_2012, Kariola_2013, Wielders_2013). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and three classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985842	SCV001134426	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000088 (10/113738 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch Syndrome (PMID: 25980754 (2015)), colorectal cancer (PMID: 27300552 (2016)), breast cancer (PMIDs: 25503501 (2015) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), and healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). Functional studies show that this variant is not damaging to protein function (PMIDs: 12522549 (2003), 21120944 (2011), 22581703 (2012) and 24040339 (2013)). 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000164048	SCV002528004	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000412287	SCV004018965	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].
All of Us Research Program, National Institutes of Health	RCV003997087	SCV004835036	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1095 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). Functional studies have found this variant to be normal in in vitro mismatch DNA repair activity, complementation of MSH6-deficient mouse embryonic stem cells and MSH6 binding (PMID: 12522549, 22581703, 17594722, 24040339). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome associated cancer and/or polyps (PMID: 12522549, 25980754, 28944238) and with early-onset breast cancer (PMID: 25503501). This variant has been identified in 12/251448 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.