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
PALB2
Final classification
Likely Benign
PALB2 c.2234A>G · p.Lys745Arg
PALB2
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
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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