ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3284G>A (p.Arg1095His) (rs63750253)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164048 SCV000214655 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-27 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 alteration has been classified as a variant of unknown significance using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1095 of the MSH6 protein (p.Arg1095His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63750253, ExAC 0.006%). This variant has been reported in the literature in individuals affected with colorectal cancer (PMID: 12522549, 25980754). ClinVar contains an entry for this variant (Variation ID: 89368). Experimental studies have shown that this missense change has no effect on MSH6 mismatch repair activity, expression, or interaction with MSH2 (PMID: 12522549, 24040339, 17594722, 22581703). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000412287 SCV000489603 uncertain significance Hereditary nonpolyposis colorectal cancer type 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 Health, Inc RCV000164048 SCV000685383 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-05 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) 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 2018-09-10 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 domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. However, multiple functional studies have found that the variant is associated with MMR activity similar to the wild-type controls (Kantelinen_2012, Kariola_2013, and Wielders_2013). The variant allele was found at a frequency of 4.5e-05 in 246222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3284G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Kariola_2013, Maxwell_2015, Wei_2016, Yurgelun_2015) with limited information (ie. lack of cosegregation and/or co-occurrence, authors classification of "neutral" or "VUS"). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, likely benign x1). 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 2019-07-12 criteria provided, single submitter clinical testing

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