ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.682C>A (p.Leu228Met) (rs751628735)

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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 RCV000163166 SCV000213684 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409697 SCV000487823 uncertain significance Lynch syndrome II 2015-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000587335 SCV000618186 uncertain significance not provided 2018-06-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.682C>A at the cDNA level, p.Leu228Met (L228M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Leu228Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Leu228Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000558825 SCV000625186 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 228 of the MLH1 protein (p.Leu228Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs751628735, ExAC 0.005%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 184050). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000163166 SCV000684859 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587335 SCV000696176 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: MLH1 c.682C>A affects a non-conserved nucleotide and results in a replacement of a Leucine (L) with a Methionine (M). Both residues are medium size and hydrophobic, therefore this Leucine to Methionine substitution does not alter the physico-chemical properties of the protein. 3/4 in silico tools predict the variant to be disease causing. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0026% which does not exceed the maximal allele frequency of a disease causing MLH1 allele (0.07%) to exclude pathogenicity. To our knowledge, the variant has not been reported in affected patients from the literature and in vitro/vivo studies to assess the functional impact of the variant have not been published either. Clinical diagnostic centers classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Due to the lack of clinical and functional data, the variant was classified as a variant of uncertain significance until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587335 SCV000889403 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202192 SCV000257114 uncertain significance not specified no assertion criteria provided research

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