The PALB2 c.104T>C (p.Leu35Pro) variant has not been observed in COSMIC and has been reported in ClinVar with an overall expert-panel classification of uncertain significance, alongside individual clinical laboratory submissions of likely pathogenic and uncertain significance.1 This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.0000619617% (1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.2 In published functional studies, p.(Leu35Pro) disrupted the BRCA1-PALB2 interaction, impaired homologous recombination and homology-directed repair, reduced RAD51 foci formation, and increased sensitivity to cisplatin and PARP inhibition, findings consistent with a damaging effect on PALB2 function.3 In silico splice prediction does not support an RNA effect, with SpliceAI showing a maximum delta score of 0.01; REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification does not use missense predictor data for PP3 or BP4.4
PALB2
Final classification
Uncertain Significance - Conflicting Evidence
PALB2 c.104T>C · p.Leu35Pro
PALB2
The PALB2 c.104T>C (p.Leu35Pro) variant has not been observed in COSMIC and has been reported in ClinVar with an overall expert-panel classification of uncertain significance, alongside individual clinical laboratory submissions of likely pathogenic and uncertain significance.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP1
Uncertain Significance - Conflicting Evidence
PALB2 c.104T>C
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
This variant is present in gnomAD v4.1 (AF= 6.19617e-07; MAF= 0.00006%, 1/1613900 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4763e-07; MAF= 0.00008%, 1/1179760 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,900
0 hom
0 hom
European (non-Finnish) 1 / 1,179,760 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.35. BayesDel score = 0.236696.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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