LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-19
Case ID: NM_024675.3_c.3089C_T_20260519_012707
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.3:c.3089C>T

PALB2  · NP_078951.2:p.(Thr1030Ile)  · NM_024675.3
GRCh37: chr16:23632707 G>A  ·  GRCh38: chr16:23621386 G>A
Gene: PALB2 Transcript: NM_024675.3
Final call
BP1 supporting PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.3
Protein
NP_078951.2:p.(Thr1030Ile)
gnomAD AF
ClinVar
Uncertain Significance
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The PALB2 c.3089C>T (p.Thr1030Ile) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current overall interpretation is uncertain significance, including an expert panel review.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its population frequency is therefore below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 thresholds.
3
In published functional studies, p.(Thr1030Ile) showed abnormal behavior in PALB2 DNA-repair assays, including protein instability, altered interactions within the BRCA2/RAD51C repair complex, marked homologous recombination defects, impaired recruitment to DNA damage sites, cytoplasmic accumulation, and increased PARP inhibitor sensitivity, consistent with a damaging effect.
4
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of 0.2; REVEL is 0.434 and BayesDel is -0.0862002, but the PALB2 expert specification does not use missense in silico scores for PP3/BP4 adjudication.
Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.
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
BA1 Not met This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%.
gnomad_v4 cspec
BS1 Not met This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%.
gnomad_v4 cspec
BS2 Not assessed No data were identified showing this variant in unaffected individuals with enough PALB2 BS2 point-based evidence to reach the required threshold.
cspec clinvar
BS3 N/A BS3 is not used in this PALB2 expert specification.
cspec
BS4 Not assessed No segregation study was identified showing lack of segregation with a LOD score or Bayes factor low enough to meet PALB2 BS4.
cspec clinvar
BP1 Met This is a missense variant, and the PALB2 expert specification directs BP1 to be applied to all missense variants.
cspec
BP2 N/A BP2 is not used in this PALB2 expert specification.
cspec
BP3 N/A BP3 is not used in this PALB2 expert specification.
cspec
BP4 N/A For PALB2, BP4 is not applied to missense variants. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the expert specification states not to use BP4 for missense variants.
cspec spliceai
BP5 N/A BP5 is not used in this PALB2 expert specification.
cspec
BP6 N/A BP6 is not used in this PALB2 expert specification.
cspec
BP7 N/A This criterion is intended for synonymous and specified intronic variants, whereas this variant is missense.
cspec
PP1 Not assessed No segregation data were identified for this variant, so there is no LOD score or Bayes factor to support PP1.
cspec clinvar
PP2 N/A PP2 is not used in this PALB2 expert specification.
cspec
PP3 Not met SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of ≥0.2.
cspec spliceai revel bayesdel
PP4 N/A PP4 is not used in this PALB2 expert specification.
cspec
PP5 N/A PP5 is not used in current expert-based variant interpretation.
cspec
PM1 N/A PM1 is not used in this PALB2 expert specification, and this variant was not identified in a statistically significant hotspot.
cspec hotspots
PM2 Met This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%.
gnomad_v4 gnomad_v2 cspec
PM3 Not assessed No proband data were identified showing this variant in trans with a pathogenic PALB2 variant in a recessive Fanconi anemia context, so PM3 cannot be assigned.
cspec clinvar
PM4 N/A PM4 is not applicable because this variant is a missense substitution rather than a stop-loss or an eligible in-frame length-changing variant under the PALB2 specification.
cspec
PM5 N/A In the PALB2 expert specification, PM5 is a truncation-cutoff rule for frameshifting, truncating, or qualifying splice variants upstream of p.Tyr1183, not a same-residue missense rule. This missense variant does not fit that framework.
cspec pm5_candidates
PM6 N/A PM6 is not used in this PALB2 expert specification.
cspec
PS1 Not met No evidence was identified that this variant has the same established splicing consequence as a previously classified pathogenic PALB2 variant, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.
cspec spliceai
PS2 N/A PS2 is not used in this PALB2 expert specification.
cspec
PS3 N/A PS3 is not used in this PALB2 expert specification, even though published functional studies have reported damaging effects for p.(Thr1030Ile).
cspec PMID:24141787 PMID:31586400
PS4 Not assessed This variant has been reported in ClinVar, but no case-control dataset, affected-case count, or odds ratio meeting the PALB2 PS4 threshold was identified.
cspec clinvar
PVS1 Not met This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1,2 splice variant, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. Available evidence does not support a loss-of-function or RNA-null mechanism for this variant, so PVS1 is not applied.
cspec pvs1_gene_context pvs1_variant_assessment spliceai
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