LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-10
Case ID: NM_024675.3_c.514_517del_20260510_032523
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.3:c.514_517del

PALB2  · NP_078951.2:p.(Ser172GlyfsTer4)  · NM_024675.3
GRCh37: chr16:23647349 CCAGA>C  ·  GRCh38: chr16:23636028 CCAGA>C
Gene: PALB2 Transcript: NM_024675.3
Final call
Pathogenic
PM2 supporting PVS1 very strong PP5 supporting PM5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.3
Protein
NP_078951.2:p.(Ser172GlyfsTer4)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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.
3
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.
4
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.
Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
BS4 Not assessed No quantitative non-segregation data, unaffected carrier data, or Bayes factor/LOD evidence were identified for this variant, so BS4 cannot be assessed.
cspec
PM4 N/A The PALB2 specification does not use PM4 for this type of variant; PM4 is reserved for stop-loss variants and not for this frameshift deletion.
cspec
PM3 Not assessed 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.
cspec PMID:17200671
BP6 N/A BP6 is not used by this VCEP.
cspec
BP5 N/A BP5 is not used by the PALB2 specification because additional molecular findings do not reliably exclude a contribution from PALB2-related cancer predisposition.
cspec
BP1 Not met 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.
cspec pvs1_variant_assessment
BS3 N/A BS3 is not used by this PALB2 specification for protein functional evidence, and no RNA-based benign evidence framework applicable to this variant was identified.
cspec
BS2 Not assessed 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.
cspec
BS1 Not met 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.
gnomad_v4 gnomad_v2 cspec
PP4 N/A PP4 is not used by the PALB2 specification for the autosomal dominant hereditary cancer presentation relevant here.
cspec
PM6 N/A PM6 is not used by the PALB2 specification.
cspec
PM2 Met 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%).
gnomad_v4 gnomad_v2 cspec
PM1 N/A PM1 is not used for PALB2 because missense pathogenic variation in defined hotspot or critical-domain settings is not an established disease mechanism in this framework.
cspec
PS4 Not assessed 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.
gnomad_v4 clinvar cspec
BA1 Not met 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.
gnomad_v4 gnomad_v2 cspec
PP1 Not assessed No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed.
cspec
PVS1 Met 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.
cspec pvs1_gene_context pvs1_variant_assessment
BP7 Not met This variant is a coding frameshift deletion rather than a synonymous or deep intronic variant, so BP7 is not met.
cspec pvs1_variant_assessment
BP4 Not met 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. Available computational evidence therefore does not support a no-impact interpretation for the gene product, and BP4 is not met.
spliceai cspec pvs1_variant_assessment
BP2 N/A BP2 is not used by the PALB2 specification.
cspec
PP2 N/A PP2 is not used for PALB2 because missense variation is not an established mechanism of disease in this framework.
cspec
PS3 N/A PS3 is not used by this PALB2 specification for protein functional evidence, and no separate RNA-based rule applicable to this variant was identified that would replace the null-variant framework already captured by PVS1.
cspec
BP3 N/A BP3 is not used for PALB2.
cspec
PP5 Met Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
PP3 Not met 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. In addition, the PALB2 specification does not use missense computational predictors for this context. PP3 is therefore not met.
spliceai cspec
PM5 Met 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.
cspec pm5_candidates pvs1_variant_assessment
PS2 N/A PS2 is not used by the PALB2 specification.
cspec
PS1 Not met This variant is a frameshift deletion, not a missense change, and no PALB2 PS1 splice-table evidence was identified for this variant. PS1 is not met.
cspec
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