ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.454-13A>G (rs267607749)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075719 SCV000106729 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Splicing abberation shown to cause skipping
Invitae RCV000524301 SCV000543548 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-08 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. This variant is not present in population databases (rs267607749, ExAC no frequency). This variant has been observed in several families affected with Lynch syndrome (LS) (PMID: 17312306, 23729658). It has also been observed to segregate with LS-associated cancer in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 90230). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing. Experimental studies have shown that this intronic change leads to exon 6 skipping, although the data was not made available for review (PMID: 23729658). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000480337 SCV000567153 likely pathogenic not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.454-13A>G or IVS5-13A>G and consists of an A>G nucleotide substitution at the -13 position of intron 5 of the MLH1 gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. However, MLH1 c.454-13A>G has been observed in the literature, internally, and at other clinical laboratories in multiple individuals with colon and/or endometrial cancers that demonstrate microsatellite instability and loss of MLH1 on immunohistochemistry (IHC), and has been shown to segregate with disease (Lagerstedt-Robinson 2007, Grandval 2012, ClinVar SCV000543548.2, ClinVar SCV000676028.1). MLH1 c.454-13A>G was not observed in large population cohorts (Lek 2016). Additionally, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). Based on currently available evidence, we consider MLH1 c.454-13A>G to be a likely pathogenic variant.
Ambry Genetics RCV000565961 SCV000676028 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
Color RCV000565961 SCV000908606 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing

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