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.1 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.2 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.3 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.4
Final classification
Uncertain Significance - Conflicting Evidence
PM2BP1
PALB2
c.3089C>T
p.Thr1030Ile
This variant
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.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: BP1 supporting, PM2 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP1
Uncertain Significance - Conflicting Evidence
PALB2 c.3089C>T
PM2 + BP1
→
Uncertain Significance - Conflicting Evidence
4
spliceai ↗revelbayesdelcspec ↗
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
PM2
supporting
review
Pathogenic
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%.
Absent from gnomAD v4.1Absent from gnomAD v2.1PALB2 PM2_Supporting threshold ≤0.000333% in gnomAD v4
BP1
supporting
review
Benign
This is a missense variant, and the PALB2 expert specification directs BP1 to be applied to all missense variants.
Variant consequence p.(Thr1030Ile)PALB2 BP1 applies to all missense variants
Assessed · not applied
· 5 not met · 5 not assessed
Pathogenic
PVS1
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.
PS1
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.
PS4
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.
PM3
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.
PP1
No segregation data were identified for this variant, so there is no LOD score or Bayes factor to support PP1.
PP3
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.
Benign
BA1
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%.
BS1
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%.
BS2
No data were identified showing this variant in unaffected individuals with enough PALB2 BS2 point-based evidence to reach the required threshold.
BS4
No segregation study was identified showing lack of segregation with a LOD score or Bayes factor low enough to meet PALB2 BS4.
N/A · 16
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
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 (4 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 232977)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.434. BayesDel score = -0.0862002.
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
Triaged references · 8 PMIDs not cited in assessment
24141787 ↗
Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
ONCOKB
19584259 ↗
PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2.
ONCOKB
19737859 ↗
Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.
ONCOKB
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
31586400 ↗
A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR