ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1559-2A>G (rs267607836)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410283 SCV000489020 pathogenic Lynch syndrome II 2016-08-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075257 SCV000592411 pathogenic Lynch syndrome 2014-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000520869 SCV000617552 pathogenic not provided 2018-04-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.1559-2A>G or IVS13-2A>G and consists of an A>Gnucleotide substitution at the -2 position of intron 13 of the MLH1 gene. Splicing assays have demonstrated that thisvariant results in skipping of exons 14 and 15 (Nakagawa 2002). This disruption is predicted to lead to either anabnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MLH1c.1559-2A>G has been observed in several families meeting Amsterdam Criteria or Bethesda Guidelines for Lynchsyndrome (Gille 2002, Nakagawa 2002, Svrcek 2010, Bonadona 2011, De Lellis 2013). Furthermore, the InternationalSociety for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic(Thompson 2014). Based on currently available evidence, we consider this variant to be pathogenic
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075257 SCV000106255 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration predicted to produce truncated protein: full inactivation of variant allele.
Invitae RCV000075257 SCV000543598 pathogenic Lynch syndrome 2016-12-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This sequence change has been reported in individuals and families with Lynch syndrome or suspected Lynch syndrome (PMID: 12183410, 12373605, 21642682, 24278394). This variant is also known as IVS13-2A>G and a>g at nt 1559-2 in the literature. An experimental study has shown that this splice site change causes skipping of exons 14 and 15, which results in an out-of-frame MLH1 transcript (PMID: 12183410). Two different variants affecting this nucleotide (c.1559-2A>C and c.1559-2A>T) have been reported in individuals and families affected with Lynch syndrome (PMID: 10200055, 24344984, 22322191, 24278394, 22949379). Experimental results also show that c.1559-2A>T results in aberrant transcripts with skipping of exon 14 and/or exon 14 and 15 (PMID: 22949379), indicating that this nucleotide is crucial for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.

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