ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1731+5G>A (rs267607850)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075328 SCV000106321 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele
Invitae RCV000075328 SCV000261840 uncertain significance Lynch syndrome 2016-10-31 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the MLH1 mRNA. It does not directly change the encoded amino acid sequence of the MLH1 protein. This variant affects a highly conserved nucleotide within the consensus splice site of intron 15. The majority of introns (75-85%) have a G at this position (PMID: 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals with Lynch syndrome (PMID: 18561205, 19685281). ClinVar contains an entry for this variant (Variation ID: 89854). Experimental studies have shown that this intronic change results in skipping of exon 15 in vitro and in RNA derived from patient cells (PMID: 18561205, 19685281). However, the effect of this exon skipping on total MLH1 RNA and protein levels in cells has not been quantified, nor has protein function been examined. In summary, this is a rare intronic change with uncertain impact on splicing and protein function. In the absence of stronger functional data or evidence of segregation with disease, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001012888 SCV001173402 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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