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
PALB2
Final classification
Likely Benign
PALB2 c.109C>A · p.Arg37Ser
PALB2
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
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 · 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