ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1103C>T (p.Ser368Leu) (rs201673334)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162449 SCV000212802 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000476166 SCV000543561 uncertain significance Hereditary nonpolyposis colon cancer 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 368 of the MLH1 protein (p.Ser368Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201673334, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 183738). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000483837 SCV000571090 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1103C>T at the cDNA level, p.Ser368Leu (S368L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. MLH1 Ser368Leu 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Ser368Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758575 SCV000887317 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1103C>T has a 14.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Color RCV000162449 SCV000911262 likely benign Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing

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