ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1572G>T (p.Met524Ile) (rs587779953)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167029 SCV000217852 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000167029 SCV000684756 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Counsyl RCV000663082 SCV000786165 uncertain significance Lynch syndrome II 2018-03-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764494 SCV000895565 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000521886 SCV000617046 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1572G>T at the cDNA level, p.Met524Ile (M524I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATT). This germline variant was observed once in a series of 1893 epithelial ovarian cancer cases (Pal 2012). MLH1 Met524Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Met524Ile is located in the region of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Met524Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459950 SCV000543582 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 524 of the MLH1 protein (p.Met524Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 187310). 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 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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