ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.588+5G>A (rs267607768)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075774 SCV000106783 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberrations: full inactivation of variant allele
Invitae RCV000627715 SCV000253792 pathogenic Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families with Lynch syndrome (PMID: 15713769, 16341550, 18561205, 24090359). This variant is also known as IVS07+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 90285). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This particular c.588+5G>A substitution in MLH1 has been reported to disrupt mRNA splicing and lead to exon skipping (PMID: 15713769, 16341550, 18561205, 24090359). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000213543 SCV000279074 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.588+5G>A or IVS7+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 7 of the MLH1 gene. Multiple RNA based assays have shown that MLH1 c.588+5G>A results in skipping of exon 7 and thus an aberrant transcript (Pagenstecher 2006, Tournier 2008, Petersen 2013). This variant has been observed in multiple individuals suspected as having Lynch syndrome; at least three of which have been reported to have a Lynch related tumor found to be MSI-H and/or show loss of MLH1 via mismatch repair immunohistochemistry (Casey 2005, Wolf 2005, Pagenstecher 2006, Batte 2014, Sunga 2017). This variant was not observed in large population cohorts (Lek 2016). Based on the current evidence, we consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075774 SCV000592364 pathogenic Lynch syndrome 2014-03-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213543 SCV000601403 pathogenic not provided 2017-01-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572458 SCV000676018 pathogenic Hereditary cancer-predisposing syndrome 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation,Deficient protein function in appropriate functional assay(s)
Fulgent Genetics,Fulgent Genetics RCV000763100 SCV000893642 pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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