ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.931A>G (p.Lys311Glu) (rs876658657)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000624023 SCV000740673 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Multifactorial probability: 0.999 but with conflicting data. Reduced classification to class 4 pending somatic information.
Ambry Genetics RCV000216819 SCV000274194 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing The p.K311E variant (also known as c.931A>G), located in coding exon 11 of the MLH1 gene, results from an A to G substitution at nucleotide position 931. The lysine at codon 311 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000473970 SCV000543638 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-06-21 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 311 of the MLH1 protein (p.Lys311Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with an MLH1-related disease from the same family in the Leiden Open-source Variation Database (PMID: 21520333), and in an individual with colon cancer in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 230595). Based on a multifactorial likelihood algorithm using genetic/in silico/statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949387). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000586755 SCV000565923 uncertain significance not provided 2020-06-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000790628 SCV000696173 uncertain significance not specified 2019-04-24 criteria provided, single submitter clinical testing Variant summary: MLH1 c.931A>G (p.Lys311Glu) results in a conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The structure of the N-terminus of human MLH1, determined by X-ray crystallography suggests that Lys311 might be a conserved basic, ATP gamma-phosphate-sensing residue (PMID 26249686). The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.931A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. On the other hand, multiple databases (LOVD, InSiGHT, UMD) reported the variant in individuals affected with colorectal cancer, and in one of these reports the variant was identified in two individuals from the same family (LOVD). However, all of the reported cases (where the age of the affected individual was provided) were older than the average age of onset for the disease (i.e. 44y). Of note, though the tumors from five tested individuals were shown to be microsatellite instable, in one case tumor immunohistochemistry demonstrated the loss of MSH2/MSH6 (InSiGHT). Therefore these data do not allow a clear conclusion about variant significance. Four other submitters, including one expert panel have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and three of them classified the variant as VUS, while the expert panel (InSiGHT) called it likely pathogenic (class 4), noting that their classification was based on multifactorial probability model, but with conflicting data. Based on the evidence outlined above, the variant was classified as uncertain significance.

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