ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.380G>A (p.Arg127Lys) (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 RCV000221216 SCV000276915 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075682 SCV000106685 pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Last base of exon; Aberrant Splicing
Invitae RCV000686990 SCV000814537 likely pathogenic Hereditary nonpolyposis colon cancer 2018-04-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 127 of the MLH1 protein (p.Arg127Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 4 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with Lynch syndrome (PMID: 11112663, 16636019, 18625694, 25559809). ClinVar contains an entry for this variant (Variation ID: 90194). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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