Submissions for variant NM_024675.4(PALB2):c.2997-1G>A

dbSNP: rs754465466

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001017865	SCV001179025	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	The c.2997-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001017865	SCV001339495	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-12-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003455099	SCV004188426	likely pathogenic	Familial cancer of breast	2023-09-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Invitae	RCV003455099	SCV004245747	uncertain significance	Familial cancer of breast	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 9 of the PALB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs754465466, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 822478). Experimental studies have shown that sequence changes at this splice site disrupt the consensus splice site and strengthen a cryptic acceptor site in exon 10, located 3 nucleotides downstream of the natural splice site. This results in an alternative transcript with an in-frame deletion of one of three consecutive glycines located in the linker region between blade 3 and blade 4, but otherwise preserves the integrity of the reading frame (PMID: 30890586). Also, this alternative transcript has been shown to occur naturally in healthy individuals (PMID: 30890586). These studies suggest that the clinical significance of this splice variant may be uncertain. 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.