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
Final classification
Uncertain Significance - Conflicting Evidence
PM2BP1
PALB2
c.104T>C
p.Leu35Pro
This variant
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 ↗
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 · 12 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 v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 6.196170766466323e-07 (0.0000619617%; 1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300000). This supports PM2 at supporting strength.
gnomAD v2.1 absentgnomAD v4.1 AF 6.196170766466323e-07PALB2 PM2 threshold <=0.000333%
BP1
supporting
review
Benign
This variant is a missense substitution, p.(Leu35Pro), and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism in PALB2.
variant consequence p.Leu35Pro missensePALB2 VCEP BP1 applies to all missense variants
Assessed · not applied
· 7 not met · 5 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.(Leu35Pro), and does not fall into the PALB2 or generic PVS1 null-variant categories.
PS1
This variant is a missense change, and the PALB2 specification states PS1 should not be used for missense variants.
PS4
This variant has been reported in ClinVar and one publication described segregation in a family with breast cancer, but no case-control study with p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk greater than or equal to 3 was identified.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be evaluated from the available data.
PM5
This variant is a missense change, and the PALB2 specification states PM5 should not be used for missense variants.
PP1
One publication states that this variant segregated in a family with a strong history of breast cancer, but no quantitative segregation data such as LOD score or Bayes factor were identified.
PP3
REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification states PP3 should not be used for missense predictor data.
Benign
BA1
The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles in the non-Finnish European population), which is far below the PALB2 BA1 threshold of greater than 0.1%.
BS1
The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles), which is below the PALB2 BS1 threshold of greater than 0.01%.
BS2
No evidence was identified showing this variant in healthy individuals meeting the PALB2 BS2 point-based framework, so BS2 cannot be assessed from the available data.
BS4
No quantitative evidence of lack of segregation such as a negative LOD score or Bayes factor was identified for this variant, so BS4 cannot be assessed from the available data.
BP4
SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splice threshold of 0.1.
N/A · 14
PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP5 · BP6 · BP7
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