The PALB2 c.109C>A (p.Arg37Ser; p.R37S) variant has been reported in ClinVar with an expert-panel classification of uncertain significance, alongside additional clinical laboratory submissions of uncertain significance and likely benign.1 This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), with a highest observed African/African American subpopulation frequency of 0.01603%, which is above the PALB2 BS1 threshold of 0.01% and below the BA1 threshold of 0.1%.2 SpliceAI predicts no meaningful splice effect for this variant (max delta score 0.00), which does not meet the PALB2 PP3 splicing threshold of 0.2 and does not support RNA-based PVS1 application.3 REVEL (0.195) and BayesDel (0.120598) were noted, but the PALB2 VCEP does not use missense protein predictors for PP3 or BP4, while BP1 is applied to PALB2 missense variants under this framework.4
Final classification
Likely Benign
BS1BP1
PALB2
c.109C>A
p.Arg37Ser
This variant
The PALB2 c.109C>A (p.Arg37Ser; p.R37S) variant has been reported in ClinVar with an expert-panel classification of uncertain significance, alongside additional clinical laboratory submissions of uncertain significance and likely benign.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP1 supporting; maps to Likely Benign.
Classification rationale
BS1BP1
Likely Benign
PALB2 c.109C>A
BS1 + BP1
→
Likely Benign
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
BS1
strong
Benign
This variant is present in gnomAD v4.1 with a highest observed subpopulation frequency of 0.01603% in the African/African American population, which is above the PALB2 BS1 threshold of 0.01%. This supports BS1 at strong strength.
gnomAD v4.1 highest subpopulation AF was 0.000160291 (12/74864 alleles0.01603%).
BP1
supporting
Benign
This is a missense variant, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense changes are thought to be exceedingly rare in PALB2 relative to truncating disease-causing variants. This supports BP1 at supporting strength.
The variant is a missense substitutionp.Arg37Ser.PALB2 VCEP applies BP1 to all missense variants.
Assessed · not applied
· 5 not met · 5 not assessed
Pathogenic
PVS1
This missense variant does not fall into a PALB2 loss-of-function variant class for default PVS1 use, and no RNA evidence or splice prediction supports a loss-of-function transcript effect.
PS1
Available evidence does not show that this variant matches a PALB2 pathogenic splicing-equivalence entry, and the PALB2 VCEP does not use PS1 for missense changes.
PS4
This variant has been reported in ClinVar, but no case-control study was identified showing a significant increase in affected individuals that meets the PALB2 PS4 threshold of p≤0.05 with OR, HR, or RR ≥3 or lower 95% CI ≥1.5.
PM2
This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), which is above the PALB2 PM2_Supporting threshold of 0.000333%.
PM3
No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 remains unassessed.
PP1
No segregation data were identified for this variant, so there is no basis to calculate the PALB2 PP1 LOD or Bayes factor thresholds.
PP3
SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2.
Benign
BA1
The highest observed gnomAD v4.1 subpopulation frequency is 0.01603% in the African/African American population, which is below the PALB2 BA1 threshold of 0.1%.
BS2
No evidence was identified showing this variant in healthy adults under the PALB2 Fanconi anemia BS2 point-based framework.
BS4
No non-segregation data were identified for this variant, so the PALB2 BS4 LOD or Bayes factor thresholds cannot be evaluated.
N/A · 16
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 9.92103e-06; MAF= 0.00099%, 16/1612736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160291; MAF= 0.01603%, 12/74864 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123047; MAF= 0.01230%, 2/16254 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00099%
· 16 / 1,612,736
0 hom · FAF 0.0092%
0 hom · FAF 0.0092%
African/African American 12 / 74,864 |
0.016% |
Admixed American 2 / 59,984 |
0.0033% |
Remaining individuals 2 / 62,440 |
0.0032% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0016%
· 4 / 251,456
0 hom · FAF 0.0021%
0 hom · FAF 0.0021%
African/African American 2 / 16,254 |
0.012% |
Admixed American 1 / 34,588 |
0.0029% |
European (non-Finnish) 1 / 113,750 |
0.00088% |
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories) and as Likely benign (1 clinical laboratory) 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 = 0.00). REVEL score = 0.195. BayesDel score = 0.120598.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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