ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1267C>A (p.Leu423Ile) (rs587781657)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000300787 SCV000430961 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics RCV000564277 SCV000664780 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-23 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000688085 SCV000815682 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 423 of the MSH6 protein (p.Leu423Ile). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and isoleucine. 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: 336442). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000564277 SCV001356942 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing

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