Submissions for variant NM_024675.4(PALB2):c.49-2A>T

dbSNP: rs786203245

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV000198571	SCV003915571	uncertain significance	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.49-2A>T variant in PALB2 occurs within the canonical splice acceptor site (-1,2) of intron 1. The computational splicing predictor SpliceAI gives a score of 0.97 for acceptor loss and 0.71 score for an acceptor gain, predicting that the variant disrupts the acceptor splice site. This alteration is predicted to result in an in-frame loss impacting two amino acids from of exon 2 in the coiled-coiled domain with unknown functional impact (PMID: 30890586, 30289697, 31159747, Ambry Genetics). This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Moderate, PM2_Supporting)
Ambry Genetics	RCV000166471	SCV000217268	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The c.49-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 2 in the PALB2 gene. This alteration was identified in 1/1824 triple-negative breast cancer patients unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11). 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. Usage of this novel acceptor site would result in an in-frame transcript lacking two highly conserved amino acids in the coiled-coiled domain and is predicted to significantly disrupt a protein-protein interface (Ambry internal data). 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.
Invitae	RCV000198571	SCV000253720	uncertain significance	Familial cancer of breast	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with PALB2-related conditions (PMID: 25452441, 29478780). ClinVar contains an entry for this variant (Variation ID: 186820). Studies have shown disruption of this splice site is associated with skipping of 2 amino acids, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 30890586, 34846068). 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.
Counsyl	RCV000198571	SCV000786004	likely pathogenic	Familial cancer of breast	2018-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000198571	SCV002579824	uncertain significance	Familial cancer of breast	2022-05-27	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000198571	SCV001192910	likely pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.