About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2524_2535delinsTCAGA, p.(Ala842SerfsTer7)
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 frameshift variant is predicted to cause p.(Ala842SerfsTer7) / p.(A842Sfs*7), introducing a premature termination codon in exon 6 of 13 and well upstream of the last exon, which is consistent with nonsense-mediated decay of a PALB2 transcript in a gene where loss of function is an established disease mechanism. Available evidence supports applying PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met.
PM5Supporting
PM5 · supporting
This variant is a truncating frameshift predicted to introduce p.(Ala842SerfsTer7), which is upstream of the PALB2 VCEP truncation cutoff at p.Tyr1183*. This supports applying PM5_Supporting under the PALB2 specification.
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, PP5 supporting, PM5 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 · 6 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.2524_2535delinsTCAGA (p.(Ala842SerfsTer7)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PALB2 PM2_Supporting population threshold of 0.000333%.
The predicted consequence is a frameshift with premature termination, p.(Ala842SerfsTer7), in a gene where loss of function is an established disease mechanism, supporting truncating-variant evidence under the PALB2 specification.
SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.10, supporting interpretation of the variant as a truncating allele rather than a splice-altering event.
No criteria match.
Met · 4
PVS1 Very strongThis frameshift variant is predicted to cause p.(Ala842SerfsTer7) / p.(A842Sfs*7), introducing a premature termination codon in exon 6 of 13 and well upstream of the last exon, which is consistent with nonsense-mediated decay of a PALB2 transcript in a gene where loss of function is an established disease mechanism. Available evidence supports applying PVS1 at very strong strength. Details ▾Hide ▴
Rule
PALB2 VCEP PVS1 decision tree; null variant in a gene where loss of function is a known disease mechanism.
Evidence considered
- PALB2 CSPEC marks PVS1 as applicable and uses a PALB2 PVS1 decision tree.
- Gene-level PVS1 context states PALB2 loss of function is an established disease mechanism.
- The variant is a frameshift with predicted protein consequence p.(Ala842SerfsTer7) / p.(A842Sfs*7)
- located in exon 6.
Still missing
- A PALB2-specific PVS1 decision-tree node was not independently reviewed beyond the retrieved CSPEC summary and variant scaffold.
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Its frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met. Details ▾Hide ▴
Rule
Frequency <=1/300,000 (0.000333%) in gnomAD v4 dataset; use as PM2_Supporting.
Evidence considered
- gnomAD v4.1: absent.
- gnomAD v2.1: absent.
- PALB2 PM2 is used at supporting strength only.
Sources
PM5 SupportingThis variant is a truncating frameshift predicted to introduce p.(Ala842SerfsTer7), which is upstream of the PALB2 VCEP truncation cutoff at p.Tyr1183*. This supports applying PM5_Supporting under the PALB2 specification. Details ▾Hide ▴
Rule
Apply PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183*.
Evidence considered
- Predicted protein consequence: p.(Ala842SerfsTer7) / p.(A842Sfs*7).
- PALB2 PM5_Supporting applies to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183*.
Sources
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Rule
Not for use by this VCEP.
Evidence considered
- PALB2 CSPEC marks PP5 as not applicable for this VCEP.
- ClinVar expert-panel classification was reviewed but not used as PP5 evidence.
- ClinVar expert panel classification
Sources
Not met · 3 · evaluated, threshold not reached
PS4 No case-control study was identified showing this exact variant is significantly enriched in affected individuals, so the PALB2 PS4 threshold is not met. Details ▾Hide ▴
Rule
Case-control studies with p-value <=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5.
Evidence considered
- PALB2 PS4 requires case-control evidence.
- ClinVar shows expert-panel classification but does not provide case-control statistics for this exact variant.
Still missing
- No exact-variant odds ratio
- relative risk
- or case-control p-value was identified.
Sources
BA1 This variant is absent from gnomAD v4.1, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.1% in gnomAD v4.
Evidence considered
- gnomAD v4.1: absent.
- PALB2 BA1 threshold: grpmax filtering allele frequency >0.1%.
Sources
BS1 This variant is absent from gnomAD v4.1, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.01% in gnomAD v4.
Evidence considered
- gnomAD v4.1: absent.
- PALB2 BS1 threshold: grpmax filtering allele frequency >0.01%.
Sources
Not assessed · 6 · no assessment recorded
PS1 No evidence was identified that this variant matches a PALB2 PS1 splicing-table entry, so PS1 was not assessed. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table.
Evidence considered
- PALB2 PS1 is used through a PALB2 splicing table and is not used for missense changes.
Still missing
- No qualifying same-effect splicing comparator was identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 point-based framework for recessive disease.
Evidence considered
- PALB2 PM3 is based on Fanconi anemia point scoring.
Still missing
- No phase-confirmed recessive observations were identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD: LOD >=0.3 / 0.6 / 1.26 or Bayes factor >=2:1 / 4:1 / 18:1; AR: segregation in 1 / 2 / >=3 affected relatives.
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence.
Still missing
- No informative family segregation
- LOD score
- or Bayes factor was identified.
Sources
BS2 No qualifying observations of this variant in healthy individuals under the PALB2 BS2 framework were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2 point-based framework for qualifying healthy observations.
Evidence considered
- PALB2 BS2 requires point-based qualifying observations and cannot be assigned from gnomAD.
Still missing
- No BS2 point-scored healthy adult observations were identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
LOD <=-0.32 / -0.64 / -1.28 or Bayes factor <=0.48 / 0.23 / 0.053:1.
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence.
Still missing
- No family study with a negative LOD score or low Bayes factor was identified.
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which is at the PALB2 BP4 splice threshold. However, BP4 was not applied because this variant has an independent frameshift truncating effect and the lack of a splice effect does not support a benign overall interpretation. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing with SpliceAI <=0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.10.
- PALB2 BP4 splice threshold is SpliceAI <=0.1.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks PS2 as not applicable.
Sources
PS3 N/APS3 is not applicable in the PALB2 VCEP framework for protein functional evidence, and no qualifying RNA assay was identified that would substitute for PVS1-based evidence. Details ▾Hide ▴
Rule
Not applicable for PALB2 protein functional evidence in this framework.
Evidence considered
- PALB2 CSPEC marks PS3 as not applicable.
- OncoKB identified literature context but no directly reviewed qualifying assay for this criterion was established here.
Sources
PM1 N/APM1 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks PM1 as not applicable.
- Cancer Hotspots did not identify a statistically significant hotspot for this variant.
Sources
PM4 N/APM4 is not applicable in the PALB2 specification for this type of variant because this criterion is reserved for stop-loss variants and not for this frameshift delins. Details ▾Hide ▴
Rule
Do not use for in-frame insertions or deletions less than a single exon; use for stop-loss variants only.
Evidence considered
- PALB2 CSPEC states PM4 is not applicable except for stop-loss variants.
Sources
PM6 N/APM6 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks PM6 as not applicable.
Sources
PP2 N/APP2 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks PP2 as not applicable.
Sources
PP3 N/APALB2 PP3 for splicing applies to silent, missense, in-frame, or non-canonical intronic variants with predicted splice impact, and this variant is a frameshift delins. SpliceAI also does not show a qualifying splice signal, with a maximum delta score of 0.10 below the PP3 threshold of 0.20. Details ▾Hide ▴
Rule
Splicing: predicted impact via splicing with SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
- Variant type: frameshift delins.
- SpliceAI max delta score = 0.10.
- PALB2 PP3 splice threshold is SpliceAI >=0.2 for specific non-canonical variant classes.
Sources
PP4 N/APP4 is not applicable for autosomal dominant PALB2-related cancer predisposition in this framework. Details ▾Hide ▴
Rule
Do not use for AD PALB2-related cancer predisposition.
Evidence considered
- PALB2 CSPEC marks PP4 as not applicable for the autosomal dominant disease context.
Sources
BS3 N/ABS3 is not applicable in the PALB2 VCEP framework for protein functional evidence, and no RNA rescue study relevant to a benign interpretation was identified. Details ▾Hide ▴
Rule
Not applicable for PALB2 protein functional evidence in this framework.
Evidence considered
- PALB2 CSPEC marks BS3 as not applicable.
Sources
BP1 N/ABP1 applies to missense variants in PALB2, and this variant is a frameshift delins, so BP1 is not applicable. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- PALB2 CSPEC applies BP1 to missense variants.
Sources
BP2 N/ABP2 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable for PALB2.
Evidence considered
- PALB2 CSPEC marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 CSPEC marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not for use by this VCEP.
Evidence considered
- PALB2 CSPEC marks BP6 as not applicable for this VCEP.
Sources
BP7 N/ABP7 applies to synonymous and deep intronic variants or RNA evidence showing lack of aberrant splicing for those classes, and this variant is a coding frameshift delins, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence for those variant classes.
Evidence considered
- PALB2 BP7 is restricted to synonymous
- deep intronic
- or corresponding RNA evidence contexts.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2524_2535delinsTCAGA
- Protein (HGVS p.)
- NP_078951.2:p.(Ala842SerfsTer7)
- GRCh38
- chr16:23629255 AGGAAGCTCTGC>TCTGA
- GRCh37
- chr16:23640576 AGGAAGCTCTGC>TCTGA
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 predicts no significant splice impact with a maximum delta score of 0.10, which is at the PALB2 BP4 splice threshold. However, BP4 was not applied because this variant has an independent frameshift truncating effect and the lack of a splice effect does not support a benign overall interpretation. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing with SpliceAI <=0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.10.
- PALB2 BP4 splice threshold is SpliceAI <=0.1.
Sources
PP3 N/APALB2 PP3 for splicing applies to silent, missense, in-frame, or non-canonical intronic variants with predicted splice impact, and this variant is a frameshift delins. SpliceAI also does not show a qualifying splice signal, with a maximum delta score of 0.10 below the PP3 threshold of 0.20. Details ▾Hide ▴
Rule
Splicing: predicted impact via splicing with SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
- Variant type: frameshift delins.
- SpliceAI max delta score = 0.10.
- PALB2 PP3 splice threshold is SpliceAI >=0.2 for specific non-canonical variant classes.
Sources
BP7 N/ABP7 applies to synonymous and deep intronic variants or RNA evidence showing lack of aberrant splicing for those classes, and this variant is a coding frameshift delins, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence for those variant classes.
Evidence considered
- PALB2 BP7 is restricted to synonymous
- deep intronic
- or corresponding RNA evidence contexts.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
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/186990/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23640576-AGGAAGCTCTGC-TCTG…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23629255-AGGAAGCTCTGC-T…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2524…
- OncoKB ↗www.oncokb.org/gene/PALB2/A842Sfs*7
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2524_2535delinsTCAGA
- 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 (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 no significant splice impact for this variant (max delta score = 0.10).
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.