ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3341T>A (p.Leu1114Gln) (rs1553331600)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566943 SCV000669979 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000586719 SCV000695861 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3341T>A (p.Leu1114Gln) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121370 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000813407 SCV000953766 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 1114 of the MSH6 protein (p.Leu1114Gln). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and glutamine. 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: 483799). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their 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.

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