ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1039-3C>G

dbSNP: rs730881737
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160524 SCV000211091 likely pathogenic not provided 2022-06-29 criteria provided, single submitter clinical testing Intronic variant demonstrated to result in abnormal splicing (External communication with Ambry); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV000764486 SCV000895557 uncertain significance Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001850268 SCV002129847 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-06 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182518). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002390389 SCV002700646 likely pathogenic Hereditary cancer-predisposing syndrome 2021-12-10 criteria provided, single submitter clinical testing The c.1039-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 12 in the MLH1 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This nucleotide position is well conserved through mammals. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000160524 SCV004226065 uncertain significance not provided 2022-04-15 criteria provided, single submitter clinical testing PP3, PM2

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