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
PALB2
Final classification
Uncertain Significance - Conflicting Evidence
PALB2 c.3089C>T · p.Thr1030Ile
PALB2
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 ↗
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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