The PALB2 NM_024675.3:c.514_517del (NP_078951.2:p.(Ser172GlyfsTer4); p.(S172Gfs*4)) variant has not been observed in somatic cancers 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 below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 thresholds.2 This deletion causes an early frameshift with a premature stop codon, and the PALB2 disease-specific framework supports loss-of-function interpretation for this null variant with PVS1_VeryStrong and PM5_Supporting for a truncating variant upstream of p.Tyr1183.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), so PP3 is not met and the interpretation is driven by the truncating effect rather than an added predicted splice defect.4
Final classification
Pathogenic
PM2PVS1PP5PM5
PALB2
c.514_517del
p.Ser172GlyfsTer4
This variant
The PALB2 NM_024675.3:c.514_517del (NP_078951.2:p.(Ser172GlyfsTer4); p.(S172Gfs*4)) variant has not been observed in somatic cancers 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: PM2 supporting, PVS1 very strong, PP5 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PM2PVS1PP5PM5
Pathogenic
PALB2 c.514_517del
PM2 + PVS1 + PP5 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
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 · 4 applied · 12 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 deletion, NM_024675.3:c.514_517del, predicted to cause p.(Ser172GlyfsTer4) [p.(S172Gfs*4)], creating a premature stop codon very early in PALB2. The PALB2 specification recognizes loss of function as an established disease mechanism and directs use of the PALB2 PVS1 decision tree for null variants; the available evidence supports full-strength PVS1 for this early truncating event.
Variant consequence: frameshift with premature stop at p.(S172Gfs*4).PALB2 loss of function is an established disease mechanism in the CSPEC/VCEP framework.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. The observed population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).
Absent from gnomAD v4.1.Absent from gnomAD v2.1.
PM5
supporting
Pathogenic
This variant is a truncating frameshift with a premature termination codon at p.(S172Gfs*4), which is far upstream of the PALB2 PM5 cutoff at p.Tyr1183*. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5_Supporting.
Variant consequence: p.(S172Gfs*4).PALB2 PM5 uses a truncation-cutoff rule rather than same-residue missense logic.
Assessed · not applied
· 7 not met · 5 not assessed
Pathogenic
PS1
This variant is a frameshift deletion, not a missense change, and no PALB2 PS1 splice-table evidence was identified for this variant.
PS4
Although PM2_Supporting is met because the variant is absent from gnomAD, no case-control study or exact-variant prevalence data were identified showing a statistically significant enrichment in affected individuals, so PS4 cannot be assessed.
PM3
No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed.
PP1
No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed.
PP3
SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 splice threshold of 0.2.
Benign
BA1
This variant is absent from gnomAD v4.1, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.
BS1
This variant is absent from gnomAD v4.1, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.
BS2
No evidence was identified showing this variant in unaffected individuals or providing the Fanconi anemia point-based observations required for BS2, so BS2 cannot be assessed.
BS4
No quantitative non-segregation data, unaffected carrier data, or Bayes factor/LOD evidence were identified for this variant, so BS4 cannot be assessed.
BP1
This variant is a frameshift deletion, not a missense variant, so it does not meet the PALB2 BP1 rule that is applied to missense variants.
BP4
SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of 0.1), but the variant still causes an early frameshift with a premature stop codon.
BP7
This variant is a coding frameshift deletion rather than a synonymous or deep intronic variant, so BP7 is not met.
N/A · 12
PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP4 · BS3 · BP2 · BP3 · BP5 · BP6
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). (ClinVarID = 461007)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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