ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1120_1122del (p.Lys374del) (rs587781660)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129805 SCV000184616 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000679213 SCV000279311 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MSH6 is denoted c.1120_1122delAAG at the cDNA level and p.Lys374del (K374del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GCTT[delAAG]GAGG. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Lysine amino acid is located within the mismatch binding domain and the nuclear localization signals (Warren 2007, Gassman 2011, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Lys374del to be a variant of uncertain significance.
Invitae RCV000233727 SCV000283701 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This variant, c.1120_1122delAAG, results in the deletion of 1 amino acid of the MSH6 protein (p.Lys374del), but otherwise preserves the integrity of the reading frame. 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: 141328). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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 RCV000129805 SCV000685167 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679213 SCV000805837 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781582 SCV000919744 uncertain significance not specified 2018-03-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1120_1122delAAG (p.Lys374del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 30954 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1120_1122delAAG in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679213 SCV001134389 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing

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