Submissions for variant NM_024675.4(PALB2):c.2514+1G>C

dbSNP: rs886039729

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255296	SCV000322679	likely pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229856	SCV001402316	likely pathogenic	Familial cancer of breast	2021-10-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 265684). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). 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	RCV002429197	SCV002741979	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	The c.2514+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 5 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 donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV001229856	SCV002761857	likely pathogenic	Familial cancer of breast	2020-06-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001229856	SCV004188453	likely pathogenic	Familial cancer of breast	2023-09-13	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.