ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.3716-4A>G

gnomAD frequency: 0.00006  dbSNP: rs777308221
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002157986 SCV002422098 likely benign Colorectal cancer, hereditary nonpolyposis, type 7 2024-04-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV004046395 SCV002619526 uncertain significance not specified 2023-03-23 criteria provided, single submitter clinical testing The c.3716-4A>G intronic variant results from an A to G substitution 4 nucleotides upstream from coding exon 7 in the MLH3 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Fulgent Genetics, Fulgent Genetics RCV005008468 SCV005635756 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-06-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004752160 SCV005345749 uncertain significance MLH3-related disorder 2024-06-03 no assertion criteria provided clinical testing The MLH3 c.3716-4A>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed in ClinVar as conflicting interpretations ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/1612328/). This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). However, the use of computer prediction programs is not equivalent to functional evidence. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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