ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1039-3C>T (rs730881737)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213179 SCV000279423 uncertain significance not provided 2016-03-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1039-3C>T or IVS11-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 11 of the MLH1 gene. Multiple in silico models predict that this variant does not impact splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 c.1039-3C>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether MLH1 c.1039-3C>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000468742 SCV000543543 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-10 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 234521). 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 is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000566363 SCV000669529 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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