The PALB2 c.3132A>T (p.Gln1044His) variant has not been identified as a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance with 5 clinical laboratory submissions.1 This variant is present in population databases, including gnomAD v4.1 at 0.00136% overall (22/1612054 alleles) with a highest observed population frequency of 0.00989% in South Asian individuals, which is above the PALB2 PM2_Supporting threshold of 0.000333% but below the BS1 threshold of 0.01% and the BA1 threshold of 0.1%.2 Computational evidence does not suggest a splice-disrupting effect, with a SpliceAI maximum delta score of 0.02, and this value is below the PALB2 PP3 splicing threshold of 0.2; additional missense predictor scores were REVEL 0.227 and BayesDel -0.259388.3
Final classification
VUS
BP1
PALB2
c.3132A>T
p.Gln1044His
This variant
The PALB2 c.3132A>T (p.Gln1044His) variant has not been identified as a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance with 5 clinical laboratory 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.3132A>T
BP1
→
VUS
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
review
Benign
This variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic PALB2 variants are predominantly truncating and true pathogenic missense variants are thought to be very uncommon.
Variant is p.(Gln1044His)a missense change.PALB2 VCEP instructs BP1 for all missense variants.
Assessed · not applied
· 5 not met · 6 not assessed
Pathogenic
PVS1
This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and the available splicing data do not show a splice-disrupting effect that would support a PVS1-based loss-of-function interpretation.
PS1
No evidence was identified that this variant produces the same established pathogenic protein or splice consequence as a previously classified PALB2 variant, and the specific PALB2 PS1 splicing-table comparison was not available in the retrieved materials.
PS4
This variant has been reported in ClinVar, but no case-control study or exact affected-versus-control enrichment statistic meeting the PALB2 PS4 threshold was identified.
PM2
This variant is present in gnomAD v4.1 at 0.00136% (22/1612054 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an informative Fanconi anemia context, so PM3 could not be assessed.
PP1
No segregation data, LOD score, or Bayes factor was identified for this variant, so PP1 could not be applied.
PP3
SpliceAI predicts no meaningful splice effect for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2, so PP3 is not met.
Benign
BA1
The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is well below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.
BS1
The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.
BS2
No qualifying observations in unaffected individuals meeting the PALB2 BS2 point-based framework were identified.
BS4
No quantitative non-segregation evidence, negative LOD score, or Bayes factor meeting the PALB2 BS4 framework was identified.
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= 1.36472e-05; MAF= 0.00136%, 22/1612054 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.89402e-05; MAF= 0.00989%, 9/90964 alleles, homozygotes = 0); grpmax FAF= 5.143e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.96851e-06; MAF= 0.00080%, 2/250988 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.55265e-05; MAF= 0.00655%, 2/30522 alleles, homozygotes = 0); grpmax FAF= 1.085e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014%
· 22 / 1,612,054
0 hom · FAF 0.0051%
0 hom · FAF 0.0051%
South Asian 9 / 90,964 |
0.0099% |
European (non-Finnish) 13 / 1,178,492 |
0.0011% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 250,988
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
South Asian 2 / 30,522 |
0.0066% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 460977)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.227. BayesDel score = -0.259388.
Functional
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.
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
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
33811135 ↗
Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore.
CLINVAR
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR