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LYFE SCIENCES
Project: HERA
NM_024675.4:c.3132A>T
p.Gln1044His  ·  PALB2
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Classification rationale
1

The PALB2 c.3132A>T (p.Gln1044His) variant has not been identified as a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance with 5 clinical laboratory submissions.

hotspots ↗ clinvar ↗
2

This variant is present in population databases, including gnomAD v4.1 at 0.00136% overall (22/1612054 alleles) with a highest observed population frequency of 0.00989% in South Asian individuals, which is above the PALB2 PM2_Supporting threshold of 0.000333% but below the BS1 threshold of 0.01% and the BA1 threshold of 0.1%.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Computational evidence does not suggest a splice-disrupting effect, with a SpliceAI maximum delta score of 0.02, and this value is below the PALB2 PP3 splicing threshold of 0.2; additional missense predictor scores were REVEL 0.227 and BayesDel -0.259388.

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= 7.96851e-06; MAF= 0.00080%, 2/250988 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.55265e-05; MAF= 0.00655%, 2/30522 alleles, homozygotes = 0); grpmax FAF= 1.085e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.36472e-05; MAF= 0.00136%, 22/1612054 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.89402e-05; MAF= 0.00989%, 9/90964 alleles, homozygotes = 0); grpmax FAF= 5.143e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 460977)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.227. BayesDel score = -0.259388.
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.
ResidueQ1044
Hotspots ↗