About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.7G>T, p.(Glu3Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
This nonsense variant, NM_024675.3:c.7G>T (p.Glu3Ter, p.E3*), introduces a premature stop codon at amino acid 3 in PALB2. The PALB2 expert specification includes gene-specific PVS1 guidance, and available gene-level context supports loss of function as an established disease mechanism, so this early truncating variant meets PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength.
PM5Supporting
PM5 · supporting
The PALB2 expert specification repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This variant creates p.Glu3Ter (p.E3*), which is far upstream of p.Tyr1183, so PM5 is met at supporting strength under the gene-specific truncation rule.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
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, PM2 supporting, PM5 supporting, PP5 supporting; maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 5 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PALB2 c.7G>T (p.Glu3Ter, p.E3*) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PALB2 PM2_Supporting population threshold of 0.000333%.
This variant introduces a premature stop codon at amino acid 3, and the active PALB2 expert specification supports loss of function as an established disease mechanism, consistent with application of PVS1 and the PALB2 truncation-based PM5 rule.
SpliceAI predicts a limited splice effect with a maximum delta score of 0.15, which is below the PALB2 PP3 threshold of 0.2 and above the BP4 threshold of 0.1, so computational splice evidence is indeterminate; a BayesDel score of 0.63 is available but is not the governing PP3/BP4 rule in this gene-specific framework.
No criteria match.
Met · 4
PVS1 Very strongThis nonsense variant, NM_024675.3:c.7G>T (p.Glu3Ter, p.E3*), introduces a premature stop codon at amino acid 3 in PALB2. The PALB2 expert specification includes gene-specific PVS1 guidance, and available gene-level context supports loss of function as an established disease mechanism, so this early truncating variant meets PVS1 at very strong strength. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; PVS1 Very Strong
Evidence considered
- NM_024675.3:c.7G>T predicts NP_078951.2:p.(Glu3Ter) / p.(E3*)
- PALB2 loss of function is an established disease mechanism in the active expert specification
- Generic PVS1 scaffold identifies this as a nonsense variant
Still missing
- The PALB2-specific PVS1 decision-tree branch for this exact very-early truncating variant was not separately extracted in the available records.
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting when frequency ≤ 1/300,000 (0.000333%) in gnomAD v4
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
Sources
PM5 SupportingThe PALB2 expert specification repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This variant creates p.Glu3Ter (p.E3*), which is far upstream of p.Tyr1183, so PM5 is met at supporting strength under the gene-specific truncation rule. Details ▾Hide ▴
Rule
PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183
Evidence considered
- PALB2 uses a truncation-cutoff PM5 rule rather than classic same-residue missense logic
- p.Glu3Ter/p.E3* is upstream of p.Tyr1183
Sources
cspec ↗pm5_candidates
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
PS1 Available evidence does not identify a PALB2 PS1 splicing-table match or another variant with the same proven RNA effect needed to apply PS1 for this variant. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table
Evidence considered
- PALB2 PS1 is governed by a splicing-specific table
- SpliceAI max delta score is 0.15
Still missing
- A PALB2 PS1 splicing-table entry specific to this variant was not identified.
Sources
PP3 For PALB2, PP3 is used for predicted splice impact when SpliceAI is at least 0.2. This variant has a SpliceAI max delta score of 0.15, which is below the 0.2 threshold, so PP3 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context. Details ▾Hide ▴
Rule
PP3 for splicing when SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.15
- BayesDel score 0.63 present but not governing under PALB2 PP3 rule
Sources
BA1 This variant is absent from gnomAD v4.1 and therefore is well below the PALB2 BA1 threshold of greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Rule
BA1 if grpmax filtering AF >0.1% in gnomAD v4
Evidence considered
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BS1 threshold of greater than 0.01%. BS1 is not met. Details ▾Hide ▴
Rule
BS1 if grpmax filtering AF >0.01% in gnomAD v4
Evidence considered
- Absent from gnomAD v4.1
Sources
BP4 For PALB2, BP4 for splice prediction requires SpliceAI of 0.1 or less. This variant has a SpliceAI max delta score of 0.15, which is above the benign threshold, so BP4 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context. Details ▾Hide ▴
Rule
BP4 for splicing when SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.15
- BayesDel score 0.63 present but not governing under PALB2 BP4 rule
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control study or exact-variant prevalence data were identified showing a significant enrichment in affected individuals that meets the PALB2 PS4 threshold. Details ▾Hide ▴
Rule
Case-control studies with p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5
Evidence considered
- ClinVar contains pathogenic submissions including expert-panel review
- Available PALB2 risk literature is gene-level or truncating-variant background rather than exact-variant PS4 evidence
Still missing
- No exact-variant odds ratio
- relative risk
- or lower 95% confidence interval was identified for this variant.
- No exact-variant case-control dataset was identified.
Sources
PM3 No confirmed in trans observations with another pathogenic PALB2 variant in individuals with Fanconi anemia were identified, so PM3 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
PM3 point-based Fanconi anemia framework
Evidence considered
- PALB2 PM3 requires Fanconi anemia point-based evidence
- No qualifying in trans observations were retrieved for this variant
Still missing
- No phase-confirmed biallelic case data were identified for this variant.
- No PM3 point-based Fanconi anemia evidence was identified.
Sources
PP1 No quantitative segregation data, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
PP1 based on quantitative co-segregation thresholds
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence
- ClinVar summary did not provide qualifying segregation metrics
Still missing
- No family segregation study with a calculable LOD score or likelihood ratio was identified.
- No affected-relative count meeting PALB2 PP1 thresholds was identified.
Sources
BS2 No qualifying observations in unaffected individuals with the point-based evidence required by the PALB2 Fanconi anemia BS2 framework were identified, so BS2 cannot be assigned. Details ▾Hide ▴
Rule
BS2 point-based Fanconi anemia framework
Evidence considered
- PALB2 BS2 requires point-based unaffected-individual evidence
Still missing
- No BS2 point-based unaffected-observation data were identified for this variant.
Sources
BS4 No quantitative non-segregation evidence, LOD score, or Bayes factor showing lack of segregation with disease was identified for this variant, so BS4 cannot be assigned. Details ▾Hide ▴
Rule
BS4 based on quantitative non-segregation thresholds
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence
- No qualifying non-segregation evidence was retrieved
Still missing
- No family study demonstrating non-segregation was identified.
- No LOD score or likelihood ratio meeting BS4 thresholds was identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not applied in the PALB2 expert specification for this disease context. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PS2 not applicable
Sources
PS3 N/APS3 is not applied in the PALB2 expert specification for this disease context, so published literature was not used to assign a PS3 strength here. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PS3 not applicable
- Curated literature links were identified but do not override the gene-specific rule
Sources
PM1 N/APM1 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PM1 not applicable
- No hotspot evidence was identified for this residue
Sources
PM4 N/APM4 is not applicable because this is a nonsense variant, and the PALB2 expert specification restricts PM4 to stop-loss variants rather than truncating variants such as this one. Details ▾Hide ▴
Rule
Use for stop-loss variants only
Evidence considered
- PALB2 PM4 is reserved for stop-loss variants
Sources
PM6 N/APM6 is not applied in the PALB2 expert specification for this disease context. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PM6 not applicable
Sources
PP2 N/APP2 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PP2 not applicable
Sources
PP4 N/APP4 is not applied for PALB2-related autosomal dominant cancer predisposition in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks PP4 not applicable
Sources
BS3 N/ABS3 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks BS3 not applicable
- Curated literature links do not override the gene-specific rule
Sources
BP1 N/ABP1 applies to missense variants in PALB2. This variant is a nonsense change, so BP1 is not applicable. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant is nonsense
- not missense
Sources
BP2 N/ABP2 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks BP2 not applicable
Sources
BP3 N/ABP3 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks BP3 not applicable
Sources
BP5 N/ABP5 is not applied for PALB2 in this expert specification. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- PALB2 expert specification marks BP5 not applicable
Sources
BP6 N/ABP6 is not applied in the PALB2 expert specification. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous and certain deep intronic variants. This variant is a nonsense substitution in the coding sequence, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA subrules as applicable
Evidence considered
- Variant is neither synonymous nor deep intronic
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.7G>T
- Protein (HGVS p.)
- NP_078951.2:p.(Glu3Ter)
- GRCh38
- chr16:23641151 C>A
- GRCh37
- chr16:23652472 C>A
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.3. Select a row to find it on the plot.
PALB2NM_024675.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PALB2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For PALB2, PP3 is used for predicted splice impact when SpliceAI is at least 0.2. This variant has a SpliceAI max delta score of 0.15, which is below the 0.2 threshold, so PP3 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context. Details ▾Hide ▴
Rule
PP3 for splicing when SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.15
- BayesDel score 0.63 present but not governing under PALB2 PP3 rule
Sources
BP4 For PALB2, BP4 for splice prediction requires SpliceAI of 0.1 or less. This variant has a SpliceAI max delta score of 0.15, which is above the benign threshold, so BP4 is not met. A BayesDel score of 0.63 is available, but the PALB2 expert specification uses the splice-prediction rule for PP3/BP4 in this context. Details ▾Hide ▴
Rule
BP4 for splicing when SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.15
- BayesDel score 0.63 present but not governing under PALB2 BP4 rule
Sources
BP7 N/ABP7 applies to synonymous and certain deep intronic variants. This variant is a nonsense substitution in the coding sequence, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA subrules as applicable
Evidence considered
- Variant is neither synonymous nor deep intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). BayesDel score = 0.63.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1526222356
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/241571/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23652472-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23641151-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.7G%3…
- OncoKB ↗www.oncokb.org/gene/PALB2/E3*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.7G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 241571)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). BayesDel score = 0.63.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.