ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.678-4A>G (rs766711342)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220973 SCV000279462 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.678-4A>G or IVS8-4A>G and consists of an A>G nucleotide substitution at the -4 position of intron 8 of the MLH1 gene. Multiple in silico models predict this variant to weaken the nearby natural acceptor site, and to possibly cause abnormal gene 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. 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 adenine (A) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether MLH1 c.678-4A>G is pathogenic or benign. We therefore consider MLH1 c.678-4A>G to be a variant of uncertain significance.
Invitae RCV000458929 SCV000543602 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the MLH1 mRNA. It does not directly change the encoded amino acid sequence of the MLH1 protein. This variant is present in population databases (rs766711342, ExAC 0.003%). This variant has been reported in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 234545). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Color RCV000579799 SCV000684858 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing

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