The PALB2 NM_024675.3:c.3362del (NP_078951.2:p.(Gly1121ValfsTer3), p.(G1121Vfs*3)) variant has been reported in ClinVar, including an expert panel likely pathogenic classification and multiple pathogenic or likely pathogenic clinical laboratory submissions.1 In gnomAD v4.1, this variant is present at 13/1,613,660 alleles (AF 0.00081%) with highest observed frequency 0.00134% in African/African American individuals; this is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2_Supporting threshold.2 Published evidence supports PALB2 as a tumor suppressor gene in which truncating variants are disease-relevant, and this frameshift is predicted to truncate the protein upstream of the PALB2 p.Tyr1183 truncation boundary used for PM5_Supporting.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.4
PALB2
Final classification
Likely Pathogenic
PALB2 c.3362del · p.Gly1121ValfsTer3
PALB2
The PALB2 NM_024675.3:c.3362del (NP_078951.2:p.(Gly1121ValfsTer3), p.(G1121Vfs*3)) variant has been reported in ClinVar, including an expert panel likely pathogenic classification and multiple pathogenic or likely pathogenic clinical laboratory submissions.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 strong, PP5 supporting, PM5 supporting; maps to Likely Pathogenic.
Classification rationale
PVS1PP5PM5
Likely Pathogenic
PALB2 c.3362del
PVS1 + PP5 + PM5
→
Likely Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentPMID:17200671 ↗PMID:21365267 ↗PMID:28779002 ↗PMID:28858227 ↗
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.05622e-06; MAF= 0.00081%, 13/1613660 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33697e-05; MAF= 0.00134%, 1/74796 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79863e-06; MAF= 0.00088%, 1/113654 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00081%
· 13 / 1,613,660
0 hom · FAF 0.00054%
0 hom · FAF 0.00054%
African/African American 1 / 74,796 |
0.0013% |
European (non-Finnish) 12 / 1,179,962 |
0.001% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0004%
· 1 / 251,320
0 hom
0 hom
European (non-Finnish) 1 / 113,654 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Likely Pathogenic 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).
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.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:17200671
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:21365267
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:28858227
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links