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LYFE SCIENCES
Project: HERA
NM_024675.3:c.3113G>A
p.Trp1038Ter  ·  PALB2
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Classification rationale
1

The PALB2 c.3113G>A (p.Trp1038Ter) variant has been reported in ClinVar with a pathogenic expert panel classification and additional pathogenic clinical laboratory submissions.

clinvar ↗
2

This variant is present in gnomAD v4 at a total allele frequency of 0.020838% and reaches 0.027778% in the highest observed population, which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.

gnomad_v4 ↗ cspec ↗
3

This variant introduces a premature termination codon and is consistent with a loss-of-function effect in PALB2, a gene for which loss of function is an established disease mechanism in the PALB2 VCEP framework.

cspec ↗
4

SpliceAI predicts splice impact with a maximum delta score of 0.74, but under PALB2-specific rules PP3 is not additionally applied for this nonsense variant type.

spliceai ↗ cspec ↗
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= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as 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 possible splice impact for this variant (max delta score = 0.74). BayesDel score = 0.63.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104552889, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueW1038
Hotspots ↗