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
Final classification
Pathogenic
PVS1PM5PP5BS1
PALB2
c.3113G>A
p.Trp1038Ter
This variant
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
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may be applied incorrectly, sources may be misread, and a confident-looking
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Gene diagram
· NM_024675.3 · variants mapped to exon structure
PALB2
NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 8 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This variant is a nonsense change predicted to result in p.(Trp1038Ter)/p.(W1038*). In the PALB2 VCEP framework, loss of function is an established disease mechanism, and the premature termination event occurs well upstream of the final exon-exon junction, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength.
NM_024675.3:c.3113G>A predicts NP_078951.2:p.(Trp1038Ter)/p.(W1038*)PALB2 CSPEC includes gene-specific PVS1 guidanceGene-level PVS1 gate is marked eligible with loss of function supported
PM5
supporting
review
Pathogenic
This truncating variant creates a premature termination codon at p.(Trp1038Ter), which is upstream of the PALB2 truncation cutoff p.Tyr1183 specified for PM5_Supporting. PM5 is met at supporting strength under the PALB2 VCEP rule.
Protein consequence p.(Trp1038Ter)/p.(W1038*)PALB2 PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Tyr1183
BS1
strong
review
Benign
This variant is present in gnomAD v4 with highest observed population allele frequency 0.0002777778 (0.027778%), which is above the PALB2 BS1 threshold of 0.01%. BS1 is met at strong strength.
gnomAD v4 highest observed population AF 0.0002777778 in NFEPALB2 BS1 threshold >0.01%
Assessed · not applied
· 2 not met · 6 not assessed
Pathogenic
PS1
PALB2 PS1 relies on a gene-specific splicing table.
PS4
This variant has been reported in ClinVar, including an expert panel pathogenic classification, but no reviewed case-control result meeting the PALB2 PS4 requirement of p-value <=0.05 with an odds ratio, hazard ratio, or relative risk >=3 or lower 95% confidence interval >=1.5 was identified here.
PM2
This variant is present in gnomAD v4 at a total allele frequency of 0.0002083848 (0.020838%) with highest observed population frequency 0.0002777778 (0.027778%) and therefore is above the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).
PM3
No reviewed evidence was identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, and no PM3 point total was available.
PP1
No quantitative co-segregation evidence meeting PALB2 PP1 thresholds was identified.
Benign
BA1
This variant does not meet the PALB2 BA1 threshold.
BS2
No reviewed evidence was identified showing this variant in healthy adults or in unaffected individuals meeting PALB2 BS2 point-based thresholds.
BS4
No quantitative non-segregation evidence meeting PALB2 BS4 thresholds was identified.
N/A · 16
PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS3 · BP1 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
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