ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1760T>C (p.Met587Thr) (rs587778945)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219130 SCV000277939 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-27 criteria provided, single submitter clinical testing Thep.M587Tvariant (also known as c.1760T>C), located in coding exon 16 of theMLH1gene, results from a T to C substitution at nucleotide position 1760. Themethionineat codon 587 is replaced bythreonine, an amino acid with similar properties. This alteration has been classified as a variant of uncertain significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This variant was not reported in population based cohorts in the following databases: Database of Single NucleotidePolymorphisms(dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be benign and deleterious by PolyPhen and SIFTin silicoanalyses, respectively. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of p.M587T remains unclear.
Invitae RCV000702649 SCV000831511 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-04-17 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 587 of the MLH1 protein (p.Met587Thr). The methionine residue is highly 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 reported in an individual in the InSiGHT database (https://www.insight-database.org/individuals/00016356). However, in that individual, a pathogenic MLH1 variant was also identified, which suggests that this c.1760T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89881). 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 disruptive, 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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