ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.23+1G>T (rs587782074)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130565 SCV000185436 likely pathogenic Hereditary cancer-predisposing syndrome 2013-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000479138 SCV000570227 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.23+1G>T or IVS1+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 1 of the PMS2 gene. This variant destroys a canonical splice donor 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 was observed in at least one individual referred for hereditary cancer testing (LaDuca 2017). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000529500 SCV000625609 likely pathogenic Hereditary nonpolyposis colon cancer 2017-07-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587782074, ExAC 0.02%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 141871). 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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