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LYFE SCIENCES
Project: HERA
NM_024675.3:c.3054G>C
p.Glu1018Asp  ·  PALB2
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Classification rationale
1

The PALB2 c.3054G>C (p.Glu1018Asp; E1018D) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.

clinvar ↗
2

This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%), which is above the PALB2 BA1 threshold of 0.1%.

gnomad_v4 ↗ cspec ↗
3

SpliceAI predicts no significant splice effect (max delta score 0.01), below the PALB2 PP3 splice threshold of 0.2; REVEL is 0.118 and BayesDel is -0.42024, and the PALB2 specification does not support missense PP3/BP4 use beyond its stated splice rules.

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
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Rule
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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= 0.000385363; MAF= 0.03854%, 109/282850 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00526263; MAF= 0.52626%, 105/19952 alleles, homozygotes = 0); grpmax FAF= 0.00444365.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000132581; MAF= 0.01326%, 214/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00416704; MAF= 0.41670%, 187/44876 alleles, homozygotes = 0); grpmax FAF= 0.00367847.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
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 = 0.01). REVEL score = 0.118. BayesDel score = -0.42024.
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; COSV55165548, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE1018
Hotspots ↗