About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.532del, p.(Glu178AsnfsTer15)
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 variant is a frameshift, NM_024675.3:c.532del, predicted to cause p.(Glu178AsnfsTer15) / p.(E178Nfs*15). PALB2 loss of function is an established disease mechanism in the applicable PALB2 VCEP framework, and this early truncating change is consistent with a loss-of-function allele; therefore PVS1 is met 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 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1 in 300,000), so PM2 is met at supporting strength.
PM5Supporting
PM5 · supporting
The PALB2 VCEP specification allows PM5_Supporting for frameshifting or truncating variants with a premature termination codon upstream of p.Tyr1183. This variant is predicted to truncate the protein at p.(Glu178AsnfsTer15) / p.(E178Nfs*15), well upstream of p.Tyr1183, so PM5 is met at supporting strength.
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 · 4 not met · 5 not assessed · 15 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.532del (p.(Glu178AsnfsTer15), p.(E178Nfs*15)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including expert panel review.
This variant is absent from gnomAD v4.1 and gnomAD v2.1, placing its observed population frequency at 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.
This variant is a frameshift predicted to generate an early truncating protein product, and PALB2 loss of function is an established disease mechanism in the applicable VCEP framework, supporting a loss-of-function interpretation.
SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05, which is below the PALB2 PP3 threshold of 0.2 and below the BP4 splice threshold of 0.1.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a frameshift, NM_024675.3:c.532del, predicted to cause p.(Glu178AsnfsTer15) / p.(E178Nfs*15). PALB2 loss of function is an established disease mechanism in the applicable PALB2 VCEP framework, and this early truncating change is consistent with a loss-of-function allele; therefore PVS1 is met at very strong strength. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- Frameshift variant with predicted premature termination
- PALB2 VCEP framework supports loss of function as a disease mechanism
Still missing
- The PALB2-specific PVS1 decision-tree node was not independently visualized in the retrieved materials.
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1 in 300,000), so PM2 is met at supporting strength. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
Sources
PM5 SupportingThe PALB2 VCEP specification allows PM5_Supporting for frameshifting or truncating variants with a premature termination codon upstream of p.Tyr1183. This variant is predicted to truncate the protein at p.(Glu178AsnfsTer15) / p.(E178Nfs*15), well upstream of p.Tyr1183, so PM5 is met at supporting strength. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183
Evidence considered
- Predicted truncation at codon 192
- PALB2 PM5 rule for upstream truncating variants
Sources
cspec ↗pvs1_variant_assessment
Not met · 4 · evaluated, threshold not reached
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05. This is below the PALB2 PP3 threshold of 0.2, so available computational evidence does not support PP3. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BA1 threshold of greater than 0.1%, and BA1 is not met. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BS1 threshold of greater than 0.01%, and BS1 is not met. Details ▾Hide ▴
BP4 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05, which is below the BP4 splice threshold of 0.1. However, this computational splice result does not override the damaging frameshift protein consequence, so BP4 is not applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.05
- Variant remains a protein-truncating frameshift
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no exact variant-specific case-control study or validated odds ratio meeting the PALB2 PS4 threshold was identified. Available evidence is insufficient to assess PS4. Details ▾Hide ▴
Evidence considered
- ClinVar pathogenic submissions
- No verified exact-variant case-control metric retrieved
Still missing
- Need exact affected-case and control counts for this variant
- Need a case-control estimate meeting p-value and effect-size thresholds
Sources
PM3 No verified evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed from the available evidence. Details ▾Hide ▴
Evidence considered
- No exact in trans or Fanconi anemia evidence retrieved for this variant
Still missing
- Need confirmed phase with a second pathogenic PALB2 variant
- Need phenotype data consistent with Fanconi anemia for PM3 point assignment
Sources
PP1 No segregation data were identified for this variant, so the LOD or Bayes factor thresholds required for PALB2 PP1 could not be evaluated. Details ▾Hide ▴
Evidence considered
- No segregation evidence retrieved
Still missing
- Need family segregation data with phenotype detail
- Need quantitative segregation analysis or qualifying affected-relative counts
Sources
BS2 No evidence was identified showing this variant in the number of unaffected or appropriately characterized individuals required for PALB2 BS2 scoring, so BS2 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No qualifying unaffected-carrier evidence retrieved
Still missing
- Need qualifying unaffected carriers with age and phenotype context
- Need point-based BS2 evidence under the PALB2 specification
Sources
BS4 No non-segregation data were identified for this variant, and the LOD or Bayes factor thresholds required for PALB2 BS4 were not available. BS4 cannot be assessed from the current evidence. Details ▾Hide ▴
Evidence considered
- No non-segregation evidence retrieved
Still missing
- Need informative family data showing lack of segregation
- Need quantitative non-segregation analysis accounting for PALB2 penetrance
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a frameshift variant, not a missense or splice-equivalent change eligible for the PALB2 PS1 splicing table, so PS1 is not applicable. Details ▾Hide ▴
PS2 N/AThe PALB2 VCEP specification does not use PS2 for this disease setting, and no confirmed de novo evidence was identified. Details ▾Hide ▴
PS3 N/AThe PALB2 VCEP specification does not apply PS3 for protein functional data in this setting, and no RNA assay evidence requiring a PVS1-strength RNA adjustment was identified here. Details ▾Hide ▴
Evidence considered
- PS3 marked not applicable in PALB2 specification
- No RNA assay evidence retrieved
Still missing
- Direct review of any variant-specific RNA study would be needed if such data exist.
Sources
PM1 N/AThe PALB2 VCEP specification does not use PM1 because missense pathogenic variation in PALB2 is not an established disease mechanism, and this variant is a frameshift rather than a hotspot-based missense change. Details ▾Hide ▴
Evidence considered
- PM1 marked not applicable in PALB2 specification
- No significant hotspot evidence identified
Sources
PM4 N/AThe PALB2 VCEP specification does not apply PM4 to frameshift variants; PM4 is reserved for stop-loss variants in this framework. Details ▾Hide ▴
Evidence considered
- PM4 marked not applicable for this variant type in PALB2 specification
Sources
PM6 N/AThe PALB2 VCEP specification does not use PM6 in this disease setting, and no assumed de novo evidence was identified. Details ▾Hide ▴
PP2 N/AThe PALB2 VCEP specification does not use PP2 because missense variation is not an established disease mechanism, and this variant is not missense. Details ▾Hide ▴
PP4 N/AThe PALB2 VCEP specification does not use PP4 for the autosomal dominant hereditary cancer setting because the phenotype is not sufficiently specific. Details ▾Hide ▴
BS3 N/AThe PALB2 VCEP specification does not apply BS3 for protein functional data in this setting, and no RNA study showing a lack of splicing impact was identified for use under the RNA-specific guidance. Details ▾Hide ▴
Evidence considered
- BS3 marked not applicable in PALB2 specification
- No RNA assay evidence retrieved
Still missing
- Direct review of variant-specific RNA studies would be needed if such data exist.
Sources
BP1 N/ABP1 in the PALB2 specification applies to missense variants. This variant is a frameshift, so BP1 is not applicable. Details ▾Hide ▴
BP2 N/AThe PALB2 VCEP specification does not use BP2 in this setting. Details ▾Hide ▴
BP3 N/AThis is not an in-frame indel in a repetitive region, and BP3 is not applicable under the PALB2 specification. Details ▾Hide ▴
BP5 N/ABP5 is not applicable under the PALB2 VCEP specification. Details ▾Hide ▴
BP6 N/ABP6 is not used by this VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants. This variant is a frameshift coding deletion, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.532del
- Protein (HGVS p.)
- NP_078951.2:p.(Glu178AsnfsTer15)
- GRCh38
- chr16:23636013 TC>T
- GRCh37
- chr16:23647334 TC>T
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 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05. This is below the PALB2 PP3 threshold of 0.2, so available computational evidence does not support PP3. Details ▾Hide ▴
BP4 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05, which is below the BP4 splice threshold of 0.1. However, this computational splice result does not override the damaging frameshift protein consequence, so BP4 is not applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.05
- Variant remains a protein-truncating frameshift
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants. This variant is a frameshift coding deletion, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
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/580962/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647334-TC-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23636013-TC-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.532d…
- OncoKB ↗www.oncokb.org/gene/PALB2/E178Nfs*15
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.532del
- 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 (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 = 0.05).
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.