About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2787_2788dup, p.(Asn930IlefsTer6)
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 duplication predicted to generate p.(Asn930IlefsTer6) [p.(N930Ifs*6)] with a premature termination codon well upstream of the last exon, which is consistent with nonsense-mediated decay. PALB2 loss of function is an established disease mechanism, and the PALB2 specification directs use of the PALB2 PVS1 decision tree, so PVS1 is met at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). It is also absent from gnomAD v2.1, supporting rarity in population databases.
PM5Supporting
PM5 · supporting
The predicted truncating effect, p.(Asn930IlefsTer6), occurs upstream of p.Tyr1183. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5 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 · 3 not met · 5 not assessed · 16 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.2787_2788dup (p.Asn930IlefsTer6; p.N930Ifs*6) variant has been reported in ClinVar as pathogenic, including an expert panel submission.
This variant is absent from gnomAD v4.1 and gnomAD v2.1, and its observed population frequency is below the PALB2 PM2_Supporting threshold of 0.000333%.
This frameshift duplication is predicted to create p.(Asn930IlefsTer6), introducing a premature termination codon consistent with loss of function in a gene where loss of function is an established disease mechanism, and it truncates the protein upstream of p.Tyr1183, supporting PVS1 and PM5_Supporting under the PALB2 specification.
SpliceAI shows a maximum delta score of 0.20, which suggests possible splice impact, but this was not applied as a separate PP3 or BP4 pathogenic criterion for this frameshift variant under the PALB2 rule set.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a frameshift duplication predicted to generate p.(Asn930IlefsTer6) [p.(N930Ifs*6)] with a premature termination codon well upstream of the last exon, which is consistent with nonsense-mediated decay. PALB2 loss of function is an established disease mechanism, and the PALB2 specification directs use of the PALB2 PVS1 decision tree, so PVS1 is met at very strong strength. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- Frameshift consequence p.(Asn930IlefsTer6)
- PALB2 loss-of-function mechanism established
- Variant occurs upstream of the terminal exon
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). It is also absent from gnomAD v2.1, supporting rarity in population databases. 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 predicted truncating effect, p.(Asn930IlefsTer6), occurs upstream of p.Tyr1183. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5 at supporting strength. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183; use PM5_Supporting
Evidence considered
- Predicted truncating variant
- Premature termination codon upstream of p.Tyr1183
Sources
cspec ↗pvs1_variant_assessment
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 3 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BA1 threshold of >0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
Sources
BP4 SpliceAI shows a maximum delta score of 0.20, which is above the PALB2 BP4 no-impact threshold of ≤0.1. This does not support benign computational evidence, so BP4 is not met. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1)
Evidence considered
- SpliceAI max delta score 0.20
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control study was identified showing a significant enrichment in affected individuals that meets the PALB2 PS4 threshold of p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- ClinVar observation only
- No qualifying case-control evidence found
Still missing
- No exact-variant case-control data were identified
- No de-duplicated affected-versus-control prevalence dataset was identified
Sources
PM3 No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with the relevant recessive Fanconi anemia phenotype, so PM3 cannot be assessed from the available data. Details ▾Hide ▴
Rule
PM3_Supporting = 1 point; PM3 = 2 points; PM3_Strong ≥4 points; PM3_VeryStrong ≥8 points
Evidence considered
- No trans observations found
- PALB2 PM3 requires Fanconi anemia point-based framework
Still missing
- No phase-confirmed in trans observation identified
- No Fanconi anemia proband scoring data identified
Sources
PP1 No segregation data were identified for this variant. The PALB2 specification requires quantitative co-segregation evidence or defined affected-relative thresholds, so PP1 cannot be applied from the available information. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 or BF ≥2:1 for supporting, LOD ≥0.60 or BF ≥4:1 for moderate, LOD ≥1.26 or BF ≥18:1 for strong
Evidence considered
- No co-segregation evidence found
Still missing
- No pedigree or meiosis data identified
- No LOD score or Bayes factor identified
Sources
BS2 No data were identified showing this variant in healthy adults or in the PALB2 recessive evidence framework at the point thresholds required for BS2, so this criterion cannot be assessed. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2 ≥4 points
Evidence considered
- No qualifying BS2 observations found
Still missing
- No healthy adult observations identified
- No BS2 point-based Fanconi anemia evidence identified
Sources
BS4 No non-segregation data were identified for this variant. The PALB2 specification requires quantitative evidence such as a negative LOD score or low Bayes factor, so BS4 cannot be applied from the available information. Details ▾Hide ▴
Rule
LOD ≤-0.32 or LR ≤0.48 for supporting; LOD ≤-0.64 or LR ≤0.23 for moderate; LOD ≤-1.28 or LR ≤0.053:1 for strong
Evidence considered
- No non-segregation evidence found
Still missing
- No affected non-carrier or unaffected carrier family data identified
- No LOD score or Bayes factor identified
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a frameshift variant, and the PALB2 PS1 rule is reserved for specific splicing comparisons rather than truncating variants of this type. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- PALB2 PS1 rule is splicing-table based
Sources
PS2 N/APS2 is not applicable because the PALB2 specification does not use de novo evidence for this context, and no informative confirmed de novo occurrence was identified. Details ▾Hide ▴
PS3 N/APS3 is not applicable under the PALB2 specification for this protein-truncating variant. No variant-specific functional assay evidence was needed beyond the PALB2 loss-of-function framework already captured by PVS1. Details ▾Hide ▴
PM1 N/APM1 is not applicable because the PALB2 specification does not use this criterion for PALB2 variants in this setting. Details ▾Hide ▴
Evidence considered
- PALB2 PM1 marked not applicable
- No hotspot evidence identified
Sources
PM4 N/APM4 is not applicable because the PALB2 specification does not use PM4 for this type of variant and reserves PM4 for stop-loss variants only. Details ▾Hide ▴
PM6 N/APM6 is not applicable because the PALB2 specification does not use assumed de novo evidence in this setting, and no relevant de novo observation was identified. Details ▾Hide ▴
PP2 N/APP2 is not applicable because the PALB2 specification does not use PP2. Details ▾Hide ▴
PP3 N/ASpliceAI shows a maximum delta score of 0.20, which reaches the PALB2 splice-prediction threshold used for PP3. However, this rule is intended for silent, missense, in-frame, or eligible intronic variants, and this frameshift variant is already captured by PVS1, so PP3 is not applied separately. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame, and eligible intronic variants outside ±1/2
Evidence considered
- SpliceAI max delta score 0.20
- Variant is frameshift and already captured by PVS1
Sources
PP4 N/APP4 is not applicable because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for use of this criterion in the autosomal dominant setting. Details ▾Hide ▴
BS3 N/ABS3 is not applicable under the PALB2 specification for this variant type. No well-established assay evidence showing no damaging effect was identified. Details ▾Hide ▴
BP1 N/ABP1 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- PALB2 BP1 applies to missense variants
Sources
BP2 N/ABP2 is not applicable because the PALB2 specification does not use this criterion in this setting, and no qualifying cis/trans observation was identified. Details ▾Hide ▴
BP3 N/ABP3 is not applicable because this is not an in-frame change in a repetitive region without known function. Details ▾Hide ▴
BP5 N/ABP5 is not applicable because the PALB2 specification does not use this criterion. Details ▾Hide ▴
BP6 N/ABP6 is not applicable because this criterion is not used by the PALB2 expert panel. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is not a synonymous or deep intronic variant, and no RNA evidence showing lack of aberrant splicing was identified. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2787_2788dup
- Protein (HGVS p.)
- NP_078951.2:p.(Asn930IlefsTer6)
- GRCh38
- chr16:23624054 T>TTA
- GRCh37
- chr16:23635375 T>TTA
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
BP4 SpliceAI shows a maximum delta score of 0.20, which is above the PALB2 BP4 no-impact threshold of ≤0.1. This does not support benign computational evidence, so BP4 is not met. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1)
Evidence considered
- SpliceAI max delta score 0.20
Sources
PP3 N/ASpliceAI shows a maximum delta score of 0.20, which reaches the PALB2 splice-prediction threshold used for PP3. However, this rule is intended for silent, missense, in-frame, or eligible intronic variants, and this frameshift variant is already captured by PVS1, so PP3 is not applied separately. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame, and eligible intronic variants outside ±1/2
Evidence considered
- SpliceAI max delta score 0.20
- Variant is frameshift and already captured by PVS1
Sources
BP7 N/ABP7 is not applicable because this is not a synonymous or deep intronic variant, and no RNA evidence showing lack of aberrant splicing was identified. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).
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/?term=NM_024675.3%3Ac.2787_2788dup
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23635375-T-TTA?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23624054-T-TTA?dataset=…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2787…
- OncoKB ↗www.oncokb.org/gene/PALB2/N930Ifs*6
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2787_2788dup
- 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 (2 clinical laboratories) 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 = 0.20).
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.