ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.677G>T (p.Arg226Leu) (rs63751711)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075810 SCV000592367 pathogenic Lynch syndrome 2015-05-06 criteria provided, single submitter clinical testing
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.
GeneKor MSA RCV000708610 SCV000821736 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
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]
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)
Invitae RCV000524313 SCV000543530 likely pathogenic Hereditary nonpolyposis colon cancer 2018-05-06 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.