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LYFE SCIENCES
Project: HERA
NM_024675.3:c.3362del
p.Gly1121ValfsTer3  ·  PALB2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗ PMID:17200671 ↗ PMID:21365267 ↗ PMID:28779002 ↗ PMID:28858227 ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueG1121
Hotspots ↗