ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1696G>A (p.Gly566Arg) (rs63749973)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131251 SCV000186213 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000212651 SCV000211280 uncertain significance not provided 2018-07-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1696G>A at the cDNA level, p.Gly566Arg (G566R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been observed in at least one individual with a history of colorectal cancer whose tumor showed microsatellite instability (MSI-H) (Kolodner 1999). Multiple functional assays have been used to assess the impact MSH6 Gly566Arg has on protein function but results have been discordant. While Kolodner et al. (1999) suggested partial loss of MMR activity in a yeast based assay and Cyr et al. (2008) reported reduced ATP binding and ATPase activities of the MSH2/MSH6 heterodimer, Kariola et al. (2002) reported repair activity similar to wild-type in an in vitro MMR complementation assay, Belvederesi et al. (2012) showed that Gly566Arg results in a nuclear distribution pattern comparable to wild-type, and Houlleberghs et al. (2017) suggest it is MMR-proficient based on functional studies in mouse embryonic stem cells. MSH6 Gly566Arg was observed at an allele frequency of 0.09% (31/33,578) in individuals of Latino ancestry in large population cohorts (Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly566Arg is located in the connector domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Gly566Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000212651 SCV000219110 benign not provided 2019-02-12 criteria provided, single submitter clinical testing
Counsyl RCV000411714 SCV000489717 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-11 criteria provided, single submitter clinical testing
Color RCV000131251 SCV000685215 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing

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