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
PALB2
Final classification
VUS
PALB2 c.3132A>T · p.Gln1044His
PALB2
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
Gene diagram
· NM_024675.4 · variants mapped to exon structure
PALB2
NM_024675.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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
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