ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2006+3A>G (rs1064793866)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486350 SCV000567221 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2006+3A>G or IVS11+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 11 of the PMS2 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. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether PMS2 c.2006+3A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574700 SCV000670759 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000574700 SCV000686174 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing
Invitae RCV000701178 SCV000829964 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 11 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 not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 419428). 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.

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