ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.882C>T (p.Leu294=) (rs63751707)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075900 SCV000106916 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Ambry Genetics RCV000574927 SCV000676021 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing Other data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV000574927 SCV000689925 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759814 SCV000889407 likely pathogenic not provided 2017-12-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075900 SCV000919655 pathogenic Lynch syndrome 2018-04-18 criteria provided, single submitter clinical testing Variant summary: MLH1 c.882C>T (p.Leu294Leu) is a synonymous variant that lies three nucleotides away from an exon-intron junction, which suggests it may interfere with proper splicing. Although 5/5 computational tools predict no significant impact on normal splicing, multiple functional studies report data showing that the variant is associated with exon 10 skipping (e.g., Soukarieh_2016), and may be due to disruption of an ESE site rather than the canonical splice signaling sequence (Auclair_2006). The variant was absent in 246400 control chromosomes. c.882C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome/HNPCC, including cosegregation with disease in a family. These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000818945 SCV000959584 likely pathogenic Hereditary nonpolyposis colon cancer 2019-01-02 criteria provided, single submitter clinical testing This sequence change affects codon 294 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome in a family (PMID: 16736289), and has been observed in individuals with Lynch syndrome (PMID: 16395668, 18561205). ClinVar contains an entry for this variant (Variation ID: 90407). Experimental studies using both patient-derived RNA and minigene assays have shown that this silent change results in exon 10 skipping of the MLH1 mRNA and may produce an absent or disrupted protein product (PMID: 16395668, 16736289, 18561205, 26247049, 26761715). 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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