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
PALB2
Final classification
VUS
PALB2 c.49-2A>T · p.?
PALB2
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
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
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= 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