ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3227G>A (p.Arg1076His) (rs779617676)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165943 SCV000216699 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-20 criteria provided, single submitter clinical testing The p.R1076H variant (also known as c.3227G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3227. The arginine at codon 1076 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed isolated loss of MSH6 on immunohistochemistry (IHC) and/or had high microsatellite instability (MSI-H) (Ambry internal data). This alteration was reported in one family from a cohort of 59 Asian families meeting Amsterdam I or Amsterdam II criteria (<span style="background-color:initial">Liu Y et al. PLoS ONE. 2014 Apr;9:e94170). This alteration has also been reported in multiple patients with a personal/family history of breast and/or ovarian cancer and was reported in an individual with pancreatic cancer​ (Wong ESY et al. NPJ Genom. Med. 2016 Jan 13;1:15003; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). Another alteration at the same amino acid position, p.R1076C, has been reported as likely pathogenic due to its identification in individuals with clinical features of hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and constitutional mismatch repair deficiency (CMMRD) syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int J Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7; Gard&egrave;s P et al. J. Immunol. 2012 Feb;188:2023-9). <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000198283 SCV000254307 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1076 of the MSH6 protein (p.Arg1076His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs779617676, ExAC 0.001%). This variant has been reported in individuals affected with Lynch syndrome, breast cancer, and pancreatic cancer (PMID: 24710284, 26898890, 28767289, external communication, Invitae). ClinVar contains an entry for this variant (Variation ID: 186361). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. This variant disrupts the p.Arg1076 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (PMID: 15483016, 16418736, 16525781, 21039432, 18409202), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588416 SCV000695845 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3227G>A (p.Arg1076His) variant located in the DNA mismatch repair MutS, core domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/121322 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). Multiple publications have cited the variant in affected individuals, observed as both germline and assumed somatic occurrences, however, co-occurrence and cosegregation data was very limited. Therefore, establishing a pathogenic or benign impact for this variant cannot be obtained with this information. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie additional clinical studies and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
University of Washington Department of Laboratory Medicine, University of Washington RCV000758680 SCV000887452 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.3227G>A has a 58.2% 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.
Color Health, Inc RCV000165943 SCV001345225 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202247 SCV000257243 uncertain significance not specified no assertion criteria provided research

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