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LYFE SCIENCES
Project: HERA
NM_024675.4:c.2329G>A
p.Asp777Asn  ·  PALB2
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Classification rationale
1

The PALB2 c.2329G>A (p.Asp777Asn; p.D777N) variant has been observed in somatic cancers in COSMIC 3 times (COSV55162903) and has not been reported in ClinVar.

clinvar ↗
2

This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with highest observed frequency in East Asian individuals at 4/44,886 alleles (AF 0.00891%) and grpmax FAF 0.00298%, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.

gnomad_v4 ↗
3

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL is low at 0.038; however, PALB2 missense specifications do not use PP3 or BP4 for missense variants.

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= 1.59089e-05; MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.16842e-05; MAF= 0.00217%, 35/1614078 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91146e-05; MAF= 0.00891%, 4/44886 alleles, homozygotes = 0); grpmax FAF= 2.977e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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).
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; COSV55162903, n = 3 times).
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueD777
Hotspots ↗