ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.116+5G>A (rs267607710)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561710 SCV000669534 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Functionally-validated splicing mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000561710 SCV000684721 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing
Counsyl RCV000663218 SCV000786404 uncertain significance Lynch syndrome II 2018-04-25 criteria provided, single submitter clinical testing
GeneDx RCV000766594 SCV000618400 uncertain significance not provided 2018-05-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.116+5G>A or IVS1+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 1 of the MLH1 gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. 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 a pathogenic or benign germline variant. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MLH1 c.116+5G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630192 SCV000751148 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-28 criteria provided, single submitter clinical testing This sequence change falls in intron 1 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 present in population databases (rs267607710, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 218011). 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. A different variant affecting this nucleotide (c.116+5G>C) has been determined to be pathogenic (PMID: 19267393, 19685281, 20937110, 15713769). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202146 SCV000257045 uncertain significance not specified no assertion criteria provided research

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