ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1148T>C (p.Met383Thr) (rs141344760)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115452 SCV000215984 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148622 SCV000190337 uncertain significance Ovarian cancer 2014-06-01 no assertion criteria provided research
Color RCV000115452 SCV000684717 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Counsyl RCV000662617 SCV000785280 uncertain significance Lynch syndrome II 2017-06-26 criteria provided, single submitter clinical testing
GeneDx RCV000656861 SCV000149361 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1148T>C at the cDNA level, p.Met383Thr (M383T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was observed in at least one individual with epithelial ovarian cancer (Pal 2012). MLH1 Met383Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Met383Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Gharavi Laboratory,Columbia University RCV000656861 SCV000920688 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000459634 SCV000543625 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 383 of the MLH1 protein (p.Met383Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with ovarian cancer, lung cancer or colorectal cancer (PMID: 23047549, 30324682). ClinVar contains an entry for this variant (Variation ID: 127609). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212532 SCV000539643 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; Absent from ExAC with good coverage, but present in ESP?; ClinVar: 3 VUS

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