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 2015-03-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000473970 SCV000543638 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-19 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). 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. 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 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.931A>G at the cDNA level, p.Lys311Glu (K311E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Lys311Glu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Lys311Glu occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Lys311Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America 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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