ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1038G>A (p.Gln346=) (rs63751715)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214854 SCV000278599 pathogenic Hereditary cancer-predisposing syndrome 2017-02-08 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,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000506818 SCV000617550 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1038G>A at the cDNA level. It is silent at the coding level, preserving a Glutamine at codon 346, and has been demonstrated to cause abnormal splicing. MLH1 c.1038G>A has been shown to cause inclusion of 59 nucleotides from intron 11, resulting in an abnormal transcript that is subject to nonsense-mediated mRNA decay (Nakagawa 2002). This variant has been reported in at least two individuals with colorectal cancer who met diagnostic criteria for Lynch syndrome (Nakagawa 2002, Jasperson 2010). The International Society for Gastrointestinal Hereditary Tumors Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). MLH1 c.1038G>A was not observed in large population cohorts (Lek 2016). Based on the current evidence, we consider MLH1 c.1038G>A to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075085 SCV000917637 likely pathogenic Lynch syndrome 2018-10-09 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1038G>A (p.Gln346Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site and two predict the variant weakens the same 5' donor site. These predictions are supported by at least one publication that reports experimental evidence that this variant affects mRNA splicing (Nakagawa_2002). The variant was absent in 245768 control chromosomes. c.1038G>A has been reported in the literature in individuals affected with Lynch Syndrome, indicating the variant may be associated with disease. Other nucleotide changes (c.1038G>C and c.1038G>T) at the same position are also reported in HNPCC patients (HGMD and literature). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075085 SCV000106074 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 RCV000629976 SCV000750932 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-15 criteria provided, single submitter clinical testing This sequence change affects codon 346 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 variant also falls at the last nucleotide of exon 11 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12183410, 19731080). ClinVar contains an entry for this variant (Variation ID: 89616). Experimental studies have shown that this silent change affects splicing, resulting in an addition of 59 nucleotides from intron 11 (PMID: 12183410). A different variant affecting this nucleotide (c.1038G>T) has been reported to segregate with Lynch syndrome in a family and has been shown to affect splicing (PMID: 19419416, 18561205). Another different variant affecting this nucleotide (c.1038G>C) has been shown to affect splicing (PMID: 16341550). This evidence suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506818 SCV000601341 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing

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