The PALB2 c.3512del (p.(Leu1171CysfsTer20), p.(L1171Cfs*20)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of 0.000333% and does not meet the BA1 (>0.1%) or BS1 (>0.01%) population thresholds.2 PALB2 loss of function is an established disease mechanism, and the PALB2 specification states that variants predicted to escape nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still receive full PVS1; this terminal frameshift alters that WD40 tail.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2 and within the BP4 splice threshold of 0.1, although that splice prediction does not remove concern for the protein-disrupting frameshift effect.4
Final classification
Likely Pathogenic
PVS1PM2
PALB2
c.3512del
p.Leu1171CysfsTer20
This variant
The PALB2 c.3512del (p.(Leu1171CysfsTer20), p.(L1171Cfs*20)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
PALB2 c.3512del
PVS1 + PM2
→
Likely Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
LYFE Sciences is an AI system, and it can make mistakes. Criteria
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 · 2 applied · 10 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This variant is a frameshift in PALB2, a gene in which loss of function is an established disease mechanism. Although the altered transcript is expected to escape nonsense-mediated decay because the change is in the terminal coding exon, the PALB2 specification states that variants escaping nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still be granted full PVS1; this frameshift alters the WD40 tail and replaces the clinically relevant terminal residues.
PALB2-specific guidance allows full PVS1 for variants predicted to escape NMD when the WD40 domain is adversely affected.The variant is a frameshift affecting the extreme C terminus of PALB2.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. It is also absent from gnomAD v2.1, supporting rarity in population databases.
Absent from gnomAD v4.1.Absent from gnomAD v2.1.
Assessed · not applied
· 6 not met · 4 not assessed
Pathogenic
PS4
Published data support PALB2 truncating variants as a risk class, but no case-control study or exact-variant enrichment data were identified for c.3512del that meet 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 has been observed in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 could not be evaluated.
PM5
The PALB2 specification applies PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.
PP1
No segregation data were identified for this variant, so the quantitative PALB2 PP1 thresholds could not be evaluated.
PP3
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.
Benign
BA1
This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BA1 threshold of group maximum filtering allele frequency >0.1%.
BS1
This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BS1 threshold of group maximum filtering allele frequency >0.01%.
BS2
No evidence was identified that this variant has been observed in the healthy-state configurations required for the PALB2 BS2 point-based framework, so BS2 could not be evaluated.
BS4
No lack-of-segregation data were identified for this variant, so the PALB2 BS4 quantitative thresholds could not be evaluated.
BP4
SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is within the PALB2 BP4 splice threshold of ≤0.1.
N/A · 16
PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · 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 Uncertain Significance 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 = 0.01).
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