ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1897-3C>T (rs748763466)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219931 SCV000279625 uncertain significance not provided 2015-11-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1897-3C>T or IVS16-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 16 of the MLH1 gene. Multiple in silico models predict this variant to either weaken the nearby natural splice acceptor site or increase use of a nearby cryptic splice acceptor site, possibly causing 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. The cytosine (C) nucleotide that is altered is not conserved. Based on currently available information, it is unclear whether MLH1 c.1897-3C>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000541606 SCV000625107 uncertain significance Hereditary nonpolyposis colon cancer 2018-04-09 criteria provided, single submitter clinical testing This sequence change falls in intron 16 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 (rs748763466, ExAC 0.009%). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 234627). 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 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.
Ambry Genetics RCV000568504 SCV000662088 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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