ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.779T>A (p.Leu260His) (rs63751283)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561786 SCV000662090 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000662376 SCV000784771 uncertain significance Lynch syndrome II 2017-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000484437 SCV000567372 uncertain significance not provided 2015-07-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.779T>A at the cDNA level, p.Leu260His (L260H) at the protein level, and results in the change of a Leucine to a Histidine (CTC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu260His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Leu260His occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Leu260His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000463982 SCV000543628 uncertain significance Hereditary nonpolyposis colon cancer 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 260 of the MLH1 protein (p.Leu260His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 405420). 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. A different missense substitution at this codon (p.Leu260Pro) has been determined to be pathogenic (PMID: 10882759, 28874130, 24362816, 27629256, 22290698). This suggests that the leucine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. 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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