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LYFE SCIENCES
Project: HERA
NM_024675.4:c.2234A>G
p.Lys745Arg  ·  PALB2
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Classification rationale
1

The PALB2 c.2234A>G (p.Lys745Arg, p.K745R) variant has been reported in ClinVar with conflicting interpretations, including uncertain significance and likely benign submissions.

clinvar ↗
2

In population data, this variant is present in gnomAD v4.1 at 13/1,614,018 alleles overall (0.00081%) with a highest observed African/African American frequency of 12/74,906 alleles (0.01602%), which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.

cspec ↗ gnomad_v4 ↗
3

Under the PALB2 specification, BP1 applies because this is a missense variant in a gene where truncating variants are the predominant established disease mechanism.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02; however, PP3 and BP4 are not applied to missense variants in the PALB2 framework.

cspec ↗ 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
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= 1.19287e-05; MAF= 0.00119%, 3/251494 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000184547; MAF= 0.01845%, 3/16256 alleles, homozygotes = 0); grpmax FAF= 4.977e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 8.05443e-06; MAF= 0.00081%, 13/1614018 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160201; MAF= 0.01602%, 12/74906 alleles, homozygotes = 0); grpmax FAF= 9.216e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (3 clinical laboratories).
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 = 0.02).
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.
ResidueK745
Hotspots ↗