Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_024675.4 | MANE Select | 4008 nt | 154–3714 |
| NM_024675.3 | RefSeq Select | 4069 nt | 201–3761 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe 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; Valenzuela-Palomo A et al. J Pathol, 2022 Mar;256:321-334). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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.
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
"This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: PALB2SplicePALB2SpliceSomaticNCBI Gene:79728|Show additional gene information Variant OverviewPALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.The PALB2 splice alteration has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: No results found
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.97 | -2 bp |
| Donor Loss (DL) | 0.2 | -61 bp |
| Acceptor Gain (AG) | 0.71 | -8 bp |
| Donor Gain (DG) | 0.0 | 342 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)