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
Final classification
Pathogenic
PVS1PM2PM5PP5
PALB2
c.2787_2788dup
p.Asn930IlefsTer6
This variant
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
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may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 8 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a frameshift duplication predicted to generate p.(Asn930IlefsTer6) [p.(N930Ifs*6)] with a premature termination codon well upstream of the last exon, which is consistent with nonsense-mediated decay. PALB2 loss of function is an established disease mechanism, and the PALB2 specification directs use of the PALB2 PVS1 decision tree, so PVS1 is met at very strong strength.
Frameshift consequence p.(Asn930IlefsTer6)PALB2 loss-of-function mechanism establishedVariant occurs upstream of the terminal exon
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). It is also absent from gnomAD v2.1, supporting rarity in population databases.
Absent from gnomAD v4.1Absent from gnomAD v2.1
PM5
supporting
Pathogenic
The predicted truncating effect, p.(Asn930IlefsTer6), occurs upstream of p.Tyr1183. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5 at supporting strength.
Predicted truncating variantPremature termination codon upstream of p.Tyr1183
Assessed · not applied
· 3 not met · 5 not assessed
Pathogenic
PS4
This variant has been reported in ClinVar, but no case-control study was identified showing a significant enrichment in affected individuals that meets the PALB2 PS4 threshold of p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5.
PM3
No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with the relevant recessive Fanconi anemia phenotype, so PM3 cannot be assessed from the available data.
PP1
No segregation data were identified for this variant.
Benign
BA1
This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BA1 threshold of >0.1%, so BA1 is not met.
BS1
This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met.
BS2
No data were identified showing this variant in healthy adults or in the PALB2 recessive evidence framework at the point thresholds required for BS2, so this criterion cannot be assessed.
BS4
No non-segregation data were identified for this variant.
BP4
SpliceAI shows a maximum delta score of 0.20, which is above the PALB2 BP4 no-impact threshold of ≤0.1.
N/A · 16
PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
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