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LYFE SCIENCES
Project: HERA
NM_024675.4:c.2863dup
p.Ser955LysfsTer2  ·  PALB2
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Classification rationale
1

The PALB2 c.2863dup (p.(Ser955LysfsTer2)) variant has not been observed in somatic cancers in COSMIC and is absent from ClinVar.

clinvar ↗
2

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.

cspec ↗ gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
3

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).

cspec ↗ PMID:18053174 ↗ PMID:28779002 ↗ PMID:28858227 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueS955
Hotspots ↗