The PALB2 NM_024675.3:c.49-2A>T (NP_078951.2:p.?) variant has been reported in ClinVar, where submissions include likely pathogenic and uncertain significance interpretations, and the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel has classified it as uncertain significance.1 This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 population thresholds.2 This variant affects a canonical splice acceptor position in a gene for which loss of function is an established disease mechanism, but the exact transcript consequence for this variant remains unresolved in the available evidence.3 Available computational evidence is mixed: SpliceAI shows a max delta score of 0.00, whereas BayesDel is 0.63, and these data do not independently resolve the splice consequence for this canonical splice-site variant.4
Final classification
VUS
PM2
PALB2
c.49-2A>T
p.?
This variant
The PALB2 NM_024675.3:c.49-2A>T (NP_078951.2:p.?) variant has been reported in ClinVar, where submissions include likely pathogenic and uncertain significance interpretations, and the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel has classified it as uncertain significance.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
PALB2 c.49-2A>T
PM2
→
VUS
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
4
spliceai ↗bayesdel
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_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
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
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (AF 0.00006%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). This supports PM2 at supporting strength.
Absent from gnomAD v2.1Present once in gnomAD v4.1 with total AF 6.198037205577738e-07
Assessed · not applied
· 2 not met · 9 not assessed
Pathogenic
PVS1
This variant affects the canonical -2 splice acceptor position in PALB2, and loss of function is an established disease mechanism for this gene.
PS1
The PALB2 specification indicates that PS1 for splice variants requires the PALB2 PS1 splicing table.
PS4
This variant has been reported in ClinVar, but no case-control study or other enrichment analysis was identified showing a statistically significant excess in affected individuals.
PM3
No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assigned.
PM5
The PALB2 specification allows PM5_Supporting for selected truncating or splice variants only when the required RNA-based and NMD-prone conditions are met.
PP1
No segregation data were identified for this variant, so the PALB2 PP1 thresholds were not met.
Benign
BA1
The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BA1 threshold of >0.1%.
BS1
The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BS1 threshold of >0.01%.
BS2
No qualifying observations in healthy individuals were identified that would allow PALB2 BS2 point assignment.
BS4
No non-segregation evidence was identified for this variant, so the PALB2 BS4 thresholds were not met.
BP4
SpliceAI shows no predicted splice impact for this variant (max delta score 0.00), which meets the PALB2 BP4 numeric threshold of ≤0.1.
N/A · 16
PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · PP5 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47909e-07; MAF= 0.00008%, 1/1179372 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,414
0 hom
0 hom
European (non-Finnish) 1 / 1,179,372 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.63.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links