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 2019-10-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position
Invitae RCV000198283 SCV000254307 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-12 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). ClinVar contains an entry for this variant (Variation ID: 186361). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 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.
Integrated Genetics/Laboratory Corporation of America 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 RCV000165943 SCV001345225 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202247 SCV000257243 uncertain significance not specified no assertion criteria provided research

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