ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.588+2T>A (rs587779024)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075771 SCV000106780 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000550590 SCV000625179 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-05-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in the literature in individuals affected with suspected Lynch syndrome (PMID: 21681552). ClinVar contains an entry for this variant (Variation ID: 90282). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075771 SCV000914315 likely pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Ambry Genetics RCV001024637 SCV001186685 pathogenic Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing The c.588+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 7 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This mutation was identified in a Brazilian individual meeting Bethesda or Amsterdam criteria whose tumor demonstrated loss of MLH1 and PMS2 by IHC analysis (Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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