ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.482C>T (p.Thr161Met) (rs763992299)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483884 SCV000570850 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.482C>T at the cDNA level, p.Thr161Met (T161M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in at least one individual with a Lynch syndrome-associated tumor and/or colon polyps (Yurgelun 2015). MLH1 Thr161Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr161Met occurs at a position that is conserved across species and is located in the ATPase domain (Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Thr161Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574536 SCV000673818 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000758571 SCV000887311 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.482C>T has a 14.6% 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.
Invitae RCV001054721 SCV001219070 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 161 of the MLH1 protein (p.Thr161Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs763992299, ExAC 0.009%). This variant has been observed in an individual with a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 421591). 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: "Benign"; 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.

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