ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.380G>T (p.Arg127Ile) (rs63751595)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569542 SCV000676020 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
GeneDx RCV000160521 SCV000211087 likely pathogenic not provided 2014-04-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.380G>T at the cDNA level, p.Arg127Ile (R127I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). Multiple in silico models predict this variant to destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, another variant at the same position, p.Arg127Lys (c.380G>A), has been reported in association with Lynch syndrome, is a published splice site mutation per HGMD (HGMD), and is classified by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSIGHT) as likely pathogenic (Scott 2001, Niessen 2006, Stenson 2013, Thompson 2014). MLH1 Arg127Ile 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 Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg127Ile occurs at a position that is highly conserved across species and is not located in a known functional domain. Based on the currently available information, we consider MLH1 Arg127Ile to be a likely pathogenic variant.
Invitae RCV000473283 SCV000543578 likely pathogenic Hereditary nonpolyposis colon cancer 2017-02-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 127 of the MLH1 protein (p.Arg127Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. It also falls at the last nucleotide of exon 4 of the MLH1 coding sequence. This variant is not present in population databases (rs63751595, ExAC no frequency). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754), and an individual affected with colorectal cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182516). 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting the same nucleotide c.380G>A (p.Arg127Lys) has been reported in several individuals and families affected with Lynch syndrome, and determined to be pathogenic (PMID: 11112663, 16636019, 18625694, 24362816, 25559809). In summary, this variant is a  rare missense change that is absent from the population, has been reported in affected individuals, and affects a nucleotide position that is known to be involved in causing disease. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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