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
Final classification
Likely Pathogenic
PVS1PP5PM5
PALB2
c.3362del
p.Gly1121ValfsTer3
This variant
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 ↗
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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 · 3 applied · 9 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
This variant is a frameshift predicted to truncate PALB2 as p.(Gly1121ValfsTer3) / p.(G1121Vfs*3). Germline loss of function is an established disease mechanism for PALB2, and the PALB2 specification directs use of a gene-specific PVS1 decision tree. Because this is a distal truncating event and the PALB2 specification separately treats truncating variants upstream of p.Tyr1183 as clinically relevant, PVS1 is applied with downgrade from Very Strong to Strong pending exact confirmation of the PALB2 decision-tree node for this late truncation.
Frameshift consequence p.(Gly1121ValfsTer3) / p.(G1121Vfs*3).PALB2 has established loss-of-function disease mechanism.PALB2 specification uses a gene-specific PVS1 decision tree for truncating variants.
PM5
supporting
Pathogenic
The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift is predicted as p.(Gly1121ValfsTer3), which truncates the protein upstream of p.Tyr1183, so PM5_Supporting is met.
Predicted protein consequence p.(Gly1121ValfsTer3) / p.(G1121Vfs*3).PALB2 PM5_Supporting rule for truncating variants upstream of p.Tyr1183.
Assessed · not applied
· 4 not met · 5 not assessed
Pathogenic
PS4
This variant has been reported in ClinVar, but no exact-variant case-control study, odds ratio, relative risk, or p-value meeting the PALB2 PS4 threshold was identified.
PM2
This variant is present in gnomAD v4.1 at 13/1,613,660 alleles (AF 0.00081%), with highest observed frequency 0.00134% in African/African American individuals.
PM3
No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia or another recessive PALB2-related presentation, so PM3 could not be applied.
PP1
No segregation data were identified for this variant, so PP1 could not be applied.
Benign
BA1
The highest observed population frequency in gnomAD v4.1 was 0.00134%, which is well below the PALB2 BA1 threshold of >0.1%, so BA1 is not met.
BS1
The highest observed population frequency in gnomAD v4.1 was 0.00134% (1/74,796 alleles in African/African American individuals), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met.
BS2
No evidence was identified showing this variant in the healthy adult context or recessive point-based framework required for BS2, so the criterion could not be assessed.
BS4
No quantitative non-segregation data were identified for this variant.
BP4
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, below the PALB2 BP4 splicing threshold of ≤0.1.
N/A · 16
PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
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.
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
PALB2 mutations in familial breast and pancreatic cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Sources & reference links