ClinVar Miner

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

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Total submissions: 8
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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 2020-09-18 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 The c.454-13A>G intronic variant results from an A to G substitution 13 nucleotides upstream from coding exon 6 in the MLH1 gene. The alteration has been reported in two families meeting Amsterdam criteria; tumor results from the colorectal cancers of each proband demonstrated high microsatellite instability (MSI-H) with loss of MLH1 protein expression on immunohistochemistry (Lagerstedt Robinson et al. J. Natl. Cancer Inst. 2007 Feb;99:291-299; Grandval P et al. Database (Oxford) 2013 May;2013:bat036). Furthermore, ex vivo splicing analysis using a pCAS splicing reporter mini gene and in vitro RT-PCR analysis revealed the alteration results in the loss of exon 6 (Grandval P et al. Database (Oxford) 2013 May;2013:bat036). This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000565961 SCV000908606 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356457 SCV001551632 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MLH1 c.454-13A>G variant was identified in 3 of 684 proband chromosomes (frequency: 0.004) from individuals or families with Lynch Syndrome (Lagerstedt-Robinson 2007, Davison 2012 PhD Thesis at University of the Witwatersrand, Tzortzatos 2015). The variant was identified in dbSNP (rs267607749) as “with likely pathogenic allele”, ClinVar (classified as likely pathogenic by InSiGHT expert panel in 2018, Invitae, Color, Ambry Genetics, and GeneDx) and UMD-LSDB (observed 1x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). In UMD-LSDB, an ex vivo splicing assay and in vitro RT-PCR have been reported to show that this variant results in the skipping of exon 6, citing Grandval 2013, although the data is not available for review. This variant has been identified by our laboratory in a patient with an MLH1- and PMS2-deficient colon tumour. This variant has also been found to segregate with disease in at least two families (Lagerstedt-Robinson 2207; Invitae internal data per ClinVar entry dated November 15, 2018). The variant occurs outside of the splicing consensus sequence and 2 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000480337 SCV001741916 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000480337 SCV001952638 pathogenic not provided no assertion criteria provided clinical testing

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