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LYFE SCIENCES
Project: HERA
NM_024675.4:c.2631G>C
p.Trp877Cys  ·  PALB2
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Legacy Engine
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Classification rationale
1

The PALB2 c.2631G>C (p.Trp877Cys, p.W877C) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by a single clinical laboratory.

2

In population data, this variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed South Asian frequency of 1/91,090 alleles (0.00110%), which is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2 under-represented subpopulation exception threshold for a singleton observation.

gnomad_v4 ↗
3

In silico splice prediction does not support a clinically significant splice effect, with a SpliceAI maximum delta score of 0.17, which is below the PALB2 PP3 threshold of 0.2.

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
BS4
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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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19513e-07; MAF= 0.00006%, 1/1614170 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09782e-05; MAF= 0.00110%, 1/91090 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
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 = 0.17).
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.
ResidueW877
Hotspots ↗