The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.2 This variant introduces a premature stop codon early in PALB2, and published PALB2 studies together with the PALB2 specification support loss of function as an established disease mechanism for hereditary cancer predisposition.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which does not support PP3 and is consistent with the primary consequence being protein truncation rather than altered splicing.4
Final classification
Pathogenic
PM2PVS1PP5PM5
PALB2
c.682C>T
p.Gln228Ter
This variant
The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM2 supporting, PVS1 very strong, PP5 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PM2PVS1PP5PM5
Pathogenic
PALB2 c.682C>T
PM2 + PVS1 + PP5 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentPMID:17200671 ↗PMID:25099575 ↗PMID:28779002 ↗
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 · 4 applied · 9 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
Pathogenic
This variant is a nonsense change predicted to introduce a premature stop codon early in PALB2. PALB2 loss of function is an established disease mechanism in the PALB2 specification, and the available evidence supports applying PVS1 at very strong strength for this truncating variant. SpliceAI shows no significant alternate splice effect prediction (max delta score 0.01), so there is no computational evidence suggesting a different primary mechanism.
Variant bucket: nonsensePALB2 LoF mechanism supported in the gene-level PVS1 contextPVS1 variant scaffold suggests default PVS1
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.
gnomAD v2.1 absentgnomAD v4.1 total AF 6.19573e-07 (0.00006%)AC 1/AN 1
PM5
supporting
Pathogenic
The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This variant introduces p.Gln228Ter, which is upstream of p.Tyr1183, so PM5_Supporting is met.
Protein consequence p.Gln228Ter (p.Q228*)PALB2 PM5_Supporting rule for truncating variants upstream of p.Tyr1183
PP5
supporting
Pathogenic
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
PALB2 PP5 is not applicable for this VCEPClinVar pathogenic assertions were not used as PP5 evidenceClinVar expert panel classification
Assessed · not applied
· 4 not met · 5 not assessed
Pathogenic
PS4
Published studies support increased cancer risk for truncating PALB2 variants as a class, but no exact variant-specific case-control dataset with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 was identified for this variant, so PS4 cannot be applied.
PM3
No biallelic Fanconi anemia case data or confirmed in trans observations with another pathogenic PALB2 variant were identified for this variant, so PM3 cannot be scored.
PP1
No family cosegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated.
PP3
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of 0.2.
Benign
BA1
The highest observed gnomAD v4.1 population frequency is 0.00008%, which is far below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.
BS1
The highest observed gnomAD v4.1 population frequency is 0.00008% (1/1,180,014 alleles in European non-Finnish), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.
BS2
No qualifying observations were identified in healthy adults that would allow point-based BS2 assessment for this variant.
BS4
No family-based nonsegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated.
BP4
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 BP4 splice threshold of 0.1.
N/A · 15
PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP4 · BS3 · BP1 · BP2 · BP3 · 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= 6.19573e-07; MAF= 0.00006%, 1/1614016 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 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 / 1,614,016
0 hom
0 hom
European (non-Finnish) 1 / 1,180,014 |
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 Pathogenic (5 clinical laboratories) and as Pathogenic 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 = 0.01). 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; COSV55168872, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Breast-cancer risk in families with mutations in PALB2.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are as
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Sources & reference links