ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1144+3A>T

dbSNP: rs1430015665
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000536187 SCV000625506 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-07-24 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 455640). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 10 have been determined to be pathogenic (PMID: 29566657, 30521064; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. 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.
Ambry Genetics RCV000573850 SCV000663565 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing The c.1144+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 10 in the PMS2 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; 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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