ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1731G>A (p.Ser577=) (rs63751657)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075331 SCV000106323 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele
Ambry Genetics RCV000132025 SCV000187084 pathogenic Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon;Deficient protein function in appropriate functional assay(s)
GeneDx RCV000202231 SCV000211116 pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1731G>A at the cDNA level. Although the variant is silent at the coding level, preserving a Serine at codon 577, in vitro functional studies demonstrated that MLH1 c.1731G>A causes aberrant splicing which induces complete skipping of exon 15, resulting in a truncated protein product (Liu 1995, Kohonen-Corish 1996, Pagenstecher 2006, Auclair 2008, Tournier 2008, Betz 2010). This variant has been identified in several individuals with Lynch syndrome, and tumor studies from many of these individuals showed microsatellite instability and complete or partial loss of MLH1 protein expression (Kohonen-Corish 1996, Pistorius 2000, Raedle 2001, Mangold 2005, Auclair 2006, Kurzawski 2006, Pagenstecher 2006, Tournier 2008, Yap 2009, Betz 2010, Jasperson 2010, Brieger 2011, De Lellis 2013, Lagerstedt-Robinson 2016). In addition, this variant was observed to segregate with Lynch-syndrome associated cancers in several families (Kohonen-Corish 1996, Plaschke 1999, Pagenstecher 2006). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on its aberrant effect on splicing (Thompson 2014). MLH1 c.1731G>A was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 1731, is conserved in mammals. Based on the currently available information, we consider MLH1 c.1731G>A to be pathogenic.
Invitae RCV000524246 SCV000284029 pathogenic Hereditary nonpolyposis colon cancer 2018-12-25 criteria provided, single submitter clinical testing This sequence change affects codon 577 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 sequence change falls at the last nucleotide of exon 15 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families with Lynch syndrome (PMID: 16341550, 15849733, 20223024, 18931482, 26300997, 14635101, 16216036) and a single family with prostate cancer (PMID: 21598002). ClinVar contains an entry for this variant (Variation ID: 89857). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Experimental evidence using mRNA isolated from patient blood as well as a reporter minigene assay shows this variant results in the skipping of exon 15 and an out-of-frame transcript causing a premature truncation of the protein (p.Ser556Argfs*14) (PMID: 16341550, 18561205, 16451135). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202231 SCV000601363 pathogenic not provided 2017-05-29 criteria provided, single submitter clinical testing
Color RCV000132025 SCV000689835 pathogenic Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing
Counsyl RCV000662481 SCV000784979 pathogenic Lynch syndrome II 2017-10-06 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202231 SCV000257060 pathogenic not provided no assertion criteria provided research

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