The PALB2 c.532del (p.(Glu178AsnfsTer15), p.(E178Nfs*15)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including expert panel review.1 This variant is absent from gnomAD v4.1 and gnomAD v2.1, placing its observed population frequency at 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.2 This variant is a frameshift predicted to generate an early truncating protein product, and PALB2 loss of function is an established disease mechanism in the applicable VCEP framework, supporting a loss-of-function interpretation.3 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05, which is below the PALB2 PP3 threshold of 0.2 and below the BP4 splice threshold of 0.1.4
PALB2
Final classification
Pathogenic
PALB2 c.532del · p.Glu178AsnfsTer15
PALB2
The PALB2 c.532del (p.(Glu178AsnfsTer15), p.(E178Nfs*15)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including expert panel review.
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, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
PALB2 c.532del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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.
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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
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