Submissions for variant NM_000535.7(PMS2):c.1144+5G>C

dbSNP: rs1783506726

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001657463	SCV001870166	likely benign	not provided	2019-02-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882743	SCV002133408	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-02-11	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: 1251526). 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 the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001657463	SCV004218939	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PMS2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV004945701	SCV005472432	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-03	criteria provided, single submitter	clinical testing	The c.1144+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 10 in the PMS2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.