ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.677G>A (p.Arg226Gln) (rs63751711)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075809 SCV000106823 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele
Ambry Genetics RCV000132197 SCV000187278 pathogenic Hereditary cancer-predisposing syndrome 2017-09-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000524312 SCV000284072 pathogenic Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 226 of the MLH1 protein (p.Arg226Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. It also falls at the last nucleotide of exon 8 of the MLH1 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with Lynch syndrome (PMID: 12624141, 8571956, 17453009, 12362047), and has been shown to segregate with disease in several families (PMID: 16341550, 15300854, 12547705). ClinVar contains an entry for this variant (Variation ID: 90318). Nucleotide substitutions at last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Multiple experimental studies have shown that this sequence change results in the skipping of exon 8 (PMID: 16341550, 15300854, 18561205, 21034533). This causes a frameshift at codon 197, introducing a premature translational stop signal (p.Gln197Argfs*8), and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202049 SCV000321896 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.677G>A at the cDNA level. Although the nucleotide substitution results in the change of an Arginine to a Glutamine at codon 226, and is also called Arg226Gln 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 the resulting missense alteration. Located at the last nucleotide of exon 8, protein and RNA-based functional studies have consistently found that this variant disrupts the adjacent natural splice donor site and results in skipping of exon 8, resulting in a frameshift (Leung 1998, Sharp 2004, Pagenstecher 2006, Tournier 2008). MLH1 c.677G>A has been reported in several individuals meeting Amsterdam criteria, segregating with disease in at least two kindreds, and with most studied tumors demonstrating microsatellite instability and/or loss of MLH1 expression (Winjen 1996, Gille 2002, Hendriks 2003, de Jong 2004, Sheng 2006, Overbeek 2007, van der Klift 2016, Lee 2017, Rohlin 2017). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014). MLH1 c.677G>A 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.
Counsyl RCV000410542 SCV000489235 pathogenic Lynch syndrome II 2016-09-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202049 SCV000601408 pathogenic not provided 2016-12-02 criteria provided, single submitter clinical testing
Color RCV000132197 SCV000684857 pathogenic Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing
Mendelics RCV000075809 SCV000838003 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075809 SCV000914317 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000075809 SCV000917644 pathogenic Lynch syndrome 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.677G>A (p.Arg226Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). 4/5 splice prediction tools predict a significant impact on normal splicing. These predictions were also confirmed by functional studies, showing that the variant which is located at the last nucleotide of exon 8, disrupts the splice donor site and leads to skipping of exon 8, resulting in a frameshift with a consequential stop codon (Sharp 2004, Pagenstecher 2006, Tournier2008). Although the variant can be found in the literature under the name of p.Arg226Gln, the consequence of the variant nucleotide change at the amino acid level is more properly described as p.Gln197ArgfsX8, as cited in the literature (Moussa 2011, Lagerstedt-Robinson 2016). The variant has been reported in several individuals with Lynch syndrome tumors, with cases of confirmed co-segregation data (Wijnen 1996, de Jong 2004, Sharp 2004, Pagenstecher 2006, Moussa 2011, Lagerstedt-Robinson 2016). This variant is absent in 245866 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202049 SCV000257113 pathogenic not provided no assertion criteria provided research

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