ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.677G>T (p.Arg226Leu) (rs63751711)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075810 SCV000106824 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation G>non-G at last base of exon with first 6 bases of the intron not GTRRGT (splicing aberration reported, but not quantified)
GeneDx RCV000160555 SCV000211133 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.677G>T at the cDNA level. Located in the last nucleotide of exon 8, it destroys a natural splice site and causes abnormal splicing. Multiple studies report, but do not quantify, aberrant splicing caused by this variant that results in skipping of exon 8 (Maliaka 1996, Kurzawski 2006, Hardt 2011). This is concordant with multiple protein and RNA analyses of an alternate variant at this position, MLH1 c.677G>A, which have consistently demonstrated that it causes complete skipping of exon 8 (Leung 1998, Sharp 2004, Pagenstecher 2006, Tournier 2008). In addition, in vitro functional assays of MLH1 c.677G>T showed reduced mismatch repair activity and possibly reduced protein expression (Takahashi 2007). MLH1 c.677G>T has been observed in multiple individuals with early-onset colorectal, endometrial, or gastric cancer whose family histories fulfilled Bethesda or Amsterdam Criteria for Hereditary Nonpolyposis Colorectal Cancer, but also in a sporadic gastric tumor (Maliaka 1996, Evans 2001, Kurzawski 2002, Bartosova 2003, Wagner 2003, Kurzawski 2006, Zavodna 2006, Alemayehu 2008, Hardt 2011, Schofield 2012, Raskin 2017, Martin-Morales 2018). Tumor testing in many of these individuals showed microsatellite instability and loss of MLH1 protein expression, and Bujalkova et al. (2008) found tumoral loss of heterozygosity. In addition, MLH1 c. 677G>T co-occurred with two other pathogenic variants, one in BRCA2 and one in MSH6, in an individual with early-onset endometrial cancer and bilinear family history (Gong 2012). Although the nucleotide substitution results in the change of an Arginine to a Leucine at codon 226, and is called Arg226Leu in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. MLH1 c.677G>T was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 677, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000524313 SCV000543530 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 226 of the MLH1 protein (p.Arg226Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. It also falls at the last nucleotide of exon 8 of the MLH1 coding sequence. This variant is not present in population databases (rs63751711, ExAC no frequency). This variant has been identified in several individuals and families affected with Lynch syndrome (PMID: 18383312, 20223024, 16830052, 8566964, 17510385, 12655568, Invitae). ClinVar contains an entry for this variant (Variation ID: 90319). Experimental studies in a human colon cancer cell based assay have shown that this missense change results in reduced MLH1 protein expression and reduced DNA mismatch repair activity (PMID: 17510385). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide has been shown to affect mRNA splicing (PMID: 16341550, 18561205, 21034533) and has been reported to segregate with disease in Lynch syndrome families (PMID: 16341550, 15300854, 12547705), indicating that this nucleotide may be crucial for normal mRNA splicing. In summary, this is a rare sequence change that affects the last nucleotide of exon 8 of the MLH1 gene. It is absent from the population and has been reported in affected individuals. While it has been shown to affect MLH1 protein function in vitro, its effect on mRNA splicing is uncertain. Without experimental evidence for a splicing defect and/or additional genetic data, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075810 SCV000592367 pathogenic Lynch syndrome 2015-05-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000708610 SCV000821736 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation is a single nucleotide substitution, resulting in the replacement of Arginine with Leucine at codon 226 of the MLH1 protein. The arginine residue is conserved among species and is located in a functional domain of the protein. There is a large physiochemical difference between leucine and leucine (Grantham Score 102).This variant has been reported in the literature in in multiple individuals affected with Lynch syndrome (PMID: 18383312, PMID: 20223024, PMID: 16830052, PMID: 12655568). Loss of MLH1 protein and microsatellite instability has been detected in many of these cases in the tumor tissue (PMID: 18772310). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. In vitro functional assays showed reduced mismatch repair activity and possibly reduced protein expression (PMID: 17510385 ).The mutation databases (ClinVar, InSiGHT) contain entries for this variant.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709741 SCV000840010 likely pathogenic Lynch syndrome II 2018-04-27 criteria provided, single submitter clinical testing A heterozygous c. 677G>T (p.Arg226Leu) pathogenic variant in the MLH1 gene was detected in this individual. This variant has been previously described as disease-causing (PMID: 18383312, 16830052, 8566964, 12655568). Therefore, we consider this variant to be likely pathogenic. [alaimo, 2018-01-24]
Ambry Genetics RCV000708610 SCV001187870 pathogenic Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Last nucleotide of exon;Rarity in general population databases (dbsnp, esp, 1000 genomes)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160555 SCV001248017 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249952 SCV001423894 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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