Submissions for variant NM_000535.7(PMS2):c.706-3C>A

dbSNP: rs1229860023

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000555024	SCV000625678	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-03-26	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 455735). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 6 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985915	SCV001134609	uncertain significance	not provided	2019-06-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025987	SCV001188283	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	The c.706-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 7 in the PMS2 gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000985915	SCV004022886	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.