ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-43C>T (rs587781459)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129394 SCV000184160 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000236388 SCV000293340 uncertain significance not provided 2016-05-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-43C>T, and describes a nucleotide substitution 43 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). This variant has been reported in at least one individual undergoing multigene hereditary cancer panel testing due to the suspicion of Lynch syndrome (Yurgelun 2015). This variant does not appear to affect the start codon or the Kozak translational consensus sequence. Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome and variants located within the 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2011, Ward 2013). This variant 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 base that is alternated, a cysteine (C), is not conserved. At this time, we consider MLH1 c.-43C>T to be a variant of uncertain significance.

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