ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.164-1G>C (rs763308607)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165585 SCV000216319 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-08 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000484767 SCV000572224 likely pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.164-1G>C or IVS2-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 2 of the PMS2 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual with colon cancer (Goodenberger 2016). Based on the currently available information, we consider PMS2 c.164-1G>C to be a likely pathogenic variant.
Counsyl RCV000576564 SCV000677817 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-03-17 criteria provided, single submitter clinical testing
Invitae RCV000792721 SCV000932033 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-09-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 25856668). ClinVar contains an entry for this variant (Variation ID: 186061). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). 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.

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