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.1 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%.2 Under the PALB2 specification, BP1 applies because this is a missense variant in a gene where truncating variants are the predominant established disease mechanism.3 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.4
Final classification
Likely Benign
BP1BS1
PALB2
c.2234A>G
p.Lys745Arg
This variant
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.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework; Rule18 applies.
Classification rationale
BP1BS1
Likely Benign
PALB2 c.2234A>G
BP1 + BS1
→
Likely Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 7 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
Benign
This variant is present in gnomAD v4.1 with a highest observed African/African American allele frequency of 0.01602% (12/74,906), which is above the PALB2 BS1 threshold of 0.01%, supporting BS1.
gnomAD v4.1 best subpopulation AF = 0.0001602008 (0.01602%)12/74906 alleles
BP1
supporting
Benign
This variant is a missense change, and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for PALB2.
NM_024675.4:c.2234A>G causes p.(Lys745Arg)a missense substitution.PALB2 VCEP BP1 rule: apply to all missense variants.
Assessed · not applied
· 2 not met · 5 not assessed
Pathogenic
PS4
ClinVar shows conflicting laboratory classifications, but no qualifying PALB2 case-control study with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 3 was identified, so PS4 cannot be assessed.
PM2
This variant is present in gnomAD v4.1 at 0.00081% (13/1,614,018 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.
PM3
No Fanconi anemia proband or confirmed in-trans data were identified, so PM3 cannot be assessed.
PP1
No informative co-segregation data were identified, so PP1 cannot be assessed.
Benign
BA1
The highest observed gnomAD v4.1 allele frequency is 0.01602% (12/74,906), which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.
BS2
No qualifying observations in unaffected adults or Fanconi-anemia-specific BS2 point data were identified, so BS2 cannot be assessed.
BS4
No quantitative segregation or lack-of-segregation data were identified, so BS4 cannot be assessed for this variant.
N/A · 19
PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00081%
· 13 / 1,614,018
0 hom · FAF 0.0092%
0 hom · FAF 0.0092%
African/African American 12 / 74,906 |
0.016% |
Remaining individuals 1 / 62,486 |
0.0016% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0012%
· 3 / 251,494
0 hom · FAF 0.005%
0 hom · FAF 0.005%
African/African American 3 / 16,256 |
0.018% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (3 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links