ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1082G>A (p.Arg361His) (rs63750440)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409637 SCV000489034 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000487116 SCV000571658 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in an individual with a personal history of hepatic and gastric cancer (Koehler 2007). MSH6 Arg361His was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Arg361His is located in the nuclear localization signals region (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg361His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567227 SCV000670019 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567227 SCV000690172 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing
Invitae RCV000701439 SCV000830240 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 361 of the MSH6 protein (p.Arg361His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63750440, ExAC 0.01%). This variant has been observed in an individual affected with hepatic and gastric cancer (PMID: 17498565). ClinVar contains an entry for this variant (Variation ID: 89168). Algorithms developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914, 26333163, 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000074629 SCV000887361 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1082G>A has a 48.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, and 0.16 to 1, generated from evidence of seeing this as a somatic mutation in three independent tumors two without loss of heterozygosity and one with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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