The PALB2 c.2863dup (p.(Ser955LysfsTer2)) variant has not been observed in somatic cancers in COSMIC and is absent from ClinVar.1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, placing the observed population frequency at 0%, below the PALB2 PM2_Supporting threshold of 0.000333% in gnomAD v4.2 Published PALB2 studies and the expert-panel specification support loss of function as an established disease mechanism for PALB2-related cancer predisposition, and this duplication is predicted to cause an early truncating frameshift, p.(Ser955LysfsTer2).3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, supporting interpretation of the primary effect as a truncating frameshift rather than an alternative splice-driven event.4
PALB2
Final classification
Pathogenic
PALB2 c.2863dup · p.Ser955LysfsTer2
PALB2
The PALB2 c.2863dup (p.(Ser955LysfsTer2)) variant has not been observed in somatic cancers in COSMIC and is absent from ClinVar.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5
Pathogenic
PALB2 c.2863dup
PVS1 + PM2 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentPMID:18053174 ↗PMID:28779002 ↗PMID:28858227 ↗
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
18053174 ↗
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
ONCOKB
28279176 ↗
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
ONCOKB
28779002 ↗
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
ONCOKB
29484706 ↗
Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes.
ONCOKB