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LYFE SCIENCES
Project: HERA
NM_024675.4:c.1960A>G
p.Ile654Val  ·  PALB2
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Classification rationale
1

The PALB2 c.1960A>G (p.Ile654Val) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission, and no expert panel classification was identified.

clinvar ↗
2

This variant is present in gnomAD v4 at 0.00043% overall (7/1,614,140 alleles) with a highest observed population frequency of 0.00769% in South Asians, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Under the PALB2 expert specification, BP1 is met because this is a missense variant in a gene for which established pathogenic variation is predominantly truncating.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01); REVEL is 0.043 and BayesDel is -0.826097, although the PALB2 expert specification does not use PP3 or BP4 for missense prediction alone.

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= 7.96324e-06; MAF= 0.00080%, 2/251154 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53296e-05; MAF= 0.00653%, 2/30614 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 4.33667e-06; MAF= 0.00043%, 7/1614140 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 7.68521e-05; MAF= 0.00769%, 7/91084 alleles, homozygotes = 0); grpmax FAF= 3.587e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 234115)
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 = 0.043. BayesDel score = -0.826097.
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.
ResidueI654
Hotspots ↗