ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.678-3T>A (rs267607785)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485557 SCV000566176 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.678-3T>A or IVS8-3T>A and consists of a T>A nucleotide substitution at the -3 position of intron 8 of the MLH1 gene. Multiple in silico models predict this variant to weaken the nearby natural splice 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 was observed in at least two individuals with a personal and/or family history of early-onset colorectal cancer, and was shown to segregate with colorectal cancers in four members of one of the families (Loader 2005, OÂ’Leary 2014). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant to be of uncertain significance due to insufficient evidence for classification (Thompson 2014). MLH1 c.678-3T>A was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project).The thymine (T) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether MLH1 c.678-3T>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000629884 SCV000750840 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-01 criteria provided, single submitter clinical testing This sequence change falls in intron 8 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 not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome-associated cancers in several families (PMID: 16379545, Invitae). This variant is also known as IVS8-3T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 90325). 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. 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.
Ambry Genetics RCV001025640 SCV001187873 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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