The PALB2 c.3113G>A (p.Trp1038Ter) variant has been reported in ClinVar with a pathogenic expert panel classification and additional pathogenic clinical laboratory submissions.1 This variant is present in gnomAD v4 at a total allele frequency of 0.020838% and reaches 0.027778% in the highest observed population, which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.2 This variant introduces a premature termination codon and is consistent with a loss-of-function effect in PALB2, a gene for which loss of function is an established disease mechanism in the PALB2 VCEP framework.3 SpliceAI predicts splice impact with a maximum delta score of 0.74, but under PALB2-specific rules PP3 is not additionally applied for this nonsense variant type.4
PALB2
Final classification
Pathogenic
PALB2 c.3113G>A · p.Trp1038Ter
PALB2
The PALB2 c.3113G>A (p.Trp1038Ter) variant has been reported in ClinVar with a pathogenic expert panel classification and additional pathogenic clinical laboratory submissions.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, BS1 strong, PM5 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM5PP5
BS1
Pathogenic
PALB2 c.3113G>A
PVS1 + PM5 + PP5 + BS1
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.021%
· 334 / 1,602,804
0 hom · FAF 0.025%
0 hom · FAF 0.025%
European (non-Finnish) 325 / 1,170,000 |
0.028% |
African/African American 5 / 74,618 |
0.0067% |
Remaining individuals 4 / 62,120 |
0.0064% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.006%
· 17 / 282,756
0 hom · FAF 0.0067%
0 hom · FAF 0.0067%
African/African American 3 / 24,968 |
0.012% |
European (non-Finnish) 14 / 129,120 |
0.011% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.74). BayesDel score = 0.63.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104552889, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links