The PALB2 c.1042C>A (p.Gln348Lys; Q348K) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions.1 This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00304% (49/1,613,732 alleles) with a highest observed population frequency of 0.00415% in European non-Finnish individuals; this is below the PALB2 BS1 threshold of 0.01% and above the PM2 threshold of 0.000333%.2 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2.3 Because this is a PALB2 missense variant, BP1 is met at supporting strength under the PALB2 specification, while PVS1 is not met because the variant is not a truncating or canonical splice-site loss-of-function change.4
Final classification
VUS
BP1
PALB2
c.1042C>A
p.Gln348Lys
This variant
The PALB2 c.1042C>A (p.Gln348Lys; Q348K) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.
Classification rationale
BP1
VUS
PALB2 c.1042C>A
BP1
→
VUS
4
cspec ↗pvs1_variant_assessmentpvs1_gene_context
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 · 1 applied · 11 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
BP1
supporting
Benign
This variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic missense variants are thought to be exceedingly rare in this gene. BP1 is met at supporting strength.
Variant is missense p.(Gln348Lys)PALB2 CSPEC: apply BP1 to all missense variants
Assessed · not applied
· 7 not met · 4 not assessed
Pathogenic
PVS1
This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1.
PS1
No evidence was identified that this variant has the same established pathogenic protein or splicing consequence as a previously classified pathogenic PALB2 variant, so PS1 is not met.
PS4
This variant has been reported in ClinVar, but no qualifying case-control evidence was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥3, or a lower 95% confidence interval ≥1.5.
PM2
Population frequency does not meet the PALB2 PM2_Supporting threshold.
PM3
No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in a proband informative for Fanconi anemia scoring, so PM3 could not be assessed.
PP1
No segregation data were identified to calculate a qualifying LOD score or Bayes factor for PALB2-related disease, so PP1 could not be assessed.
PP3
SpliceAI predicts no splice effect for this variant, with a maximum delta score of 0.00.
Benign
BA1
Population frequency is far below the PALB2 BA1 threshold.
BS1
Population frequency does not reach the PALB2 BS1 threshold.
BS2
No qualifying observations were identified in unaffected individuals that would permit point-based BS2 scoring under the PALB2 Fanconi anemia framework.
BS4
No quantitative non-segregation data were identified to calculate a qualifying LOD score or Bayes factor, so BS4 could not be assessed.
N/A · 16
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS3 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.03644e-05; MAF= 0.00304%, 49/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.15285e-05; MAF= 0.00415%, 49/1179912 alleles, homozygotes = 0); grpmax FAF= 3.179e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.89383e-05; MAF= 0.00389%, 11/282498 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.52832e-05; MAF= 0.00853%, 11/128982 alleles, homozygotes = 0); grpmax FAF= 4.742e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.003%
· 49 / 1,613,732
0 hom · FAF 0.0032%
0 hom · FAF 0.0032%
European (non-Finnish) 49 / 1,179,912 |
0.0042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0039%
· 11 / 282,498
0 hom · FAF 0.0047%
0 hom · FAF 0.0047%
European (non-Finnish) 11 / 128,982 |
0.0085% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.02. BayesDel score = -0.53199.
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