ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.24-3T>C (rs749485884)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228314 SCV000285119 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-18 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs749485884, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 237907). 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 is not likely to affect RNA splicing, 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.
Color Health, Inc RCV000775371 SCV000909686 likely benign Hereditary cancer-predisposing syndrome 2017-05-29 criteria provided, single submitter clinical testing
GeneDx RCV000828153 SCV000969835 likely benign not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000775371 SCV001176397 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-06 criteria provided, single submitter clinical testing The c.24-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 2 in the PMS2 gene. This nucleotide position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to weaken the efficiency of the native splice acceptor site, but is not predicted to have a deleterious effect on this splice acceptor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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