ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2002G>A (p.Glu668Lys) (rs63750292)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167113 SCV000217943 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000460446 SCV000543665 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 668 of the MLH1 protein (p.Glu668Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs63750292, ExAC 0.002%). While this variant has been published in the literature (PMID: 11474654), it has not been reported in the germline of individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 187389). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MLH1 gene (PMID: 22290698), all suggest that this missense change is likely to be tolerated, 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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