ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1999G>C (p.Asp667His) (rs151086192)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160675 SCV000211286 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1999G>C at the cDNA level, p.Asp667His (D667H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp667His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in Surface loops of the Connector domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Asp667His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214441 SCV000276953 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000233389 SCV000283738 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 667 of the MSH6 protein (p.Asp667His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182630). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). 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.
Counsyl RCV000662835 SCV000785693 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-11-01 criteria provided, single submitter clinical testing
Color RCV000214441 SCV000904017 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-25 criteria provided, single submitter clinical testing

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