The PALB2 c.2787_2788dup (p.Asn930IlefsTer6; p.N930Ifs*6) variant has been reported in ClinVar as pathogenic, including an expert panel submission.1 This variant is absent from gnomAD v4.1 and gnomAD v2.1, and its observed population frequency is below the PALB2 PM2_Supporting threshold of 0.000333%.2 This frameshift duplication is predicted to create p.(Asn930IlefsTer6), introducing a premature termination codon consistent with loss of function in a gene where loss of function is an established disease mechanism, and it truncates the protein upstream of p.Tyr1183, supporting PVS1 and PM5_Supporting under the PALB2 specification.3 SpliceAI shows a maximum delta score of 0.20, which suggests possible splice impact, but this was not applied as a separate PP3 or BP4 pathogenic criterion for this frameshift variant under the PALB2 rule set.4
PALB2
Final classification
Pathogenic
PALB2 c.2787_2788dup · p.Asn930IlefsTer6
PALB2
The PALB2 c.2787_2788dup (p.Asn930IlefsTer6; p.N930Ifs*6) variant has been reported in ClinVar as pathogenic, including an expert panel submission.
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.2787_2788dup
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 (2 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).
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