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
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
Ambry Genetics RCV000214854 SCV000278599 pathogenic Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing The c.1038G>A pathogenic mutation (also known as p.Q346Q), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 1038. This nucleotide substitution does not change the glutamine at codon 346. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in an individual with a microsatellite unstable colorectal carcinoma who fulfilled Amsterdam criteria for Lynch syndrome. Based on RNA studies, this mutation resulted in the activation of a cryptic donor splice site and inclusion of 59 intronic nucleotides, which is predicted to result in a translational frameshift (Nakagawa H et al Cancer Res. 2002 Aug;62(16):4579-82; Ambry internal data). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at []). Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506818 SCV000601341 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing
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.
Invitae RCV000629976 SCV000750932 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-26 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12183410, 19731080). ClinVar contains an entry for this variant (Variation ID: 89616). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with aberrant splicing, which introduces a frameshift (PMID: 12183410). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.1038 nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18561205, 16341550, 19419416). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.

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