ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1038+5G>T

dbSNP: rs780419140
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001227001 SCV001399335 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-04 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in an individual with Lynch syndrome related cancers in the Universal Mutation Database (PMID: 10612827). However, in that individual pathogenic allele[s] were also identified in MLH1, which suggests that this c.1038+5G>T variant was not the primary cause of disease. This variant is present in population databases (rs780419140, ExAC 0.005%). 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, but it affects a nucleotide within the consensus splice site of the intron.
Baylor Genetics RCV004570558 SCV005057981 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2024-02-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004944909 SCV005448483 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-05 criteria provided, single submitter clinical testing The c.1038+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 11 in the MLH1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear.

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