About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1058A>T, p.(Lys353Ile)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed gnomAD v4.1 allele frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2_Supporting is met.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for this gene.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: BP1 supporting, PM2 supporting; maps to Uncertain Significance - Conflicting Evidence.
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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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: 2 met · 2 not met · 5 not assessed · 19 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.1058A>T (p.Lys353Ile) variant has been reported in ClinVar as uncertain significance by a single submitter.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its gnomAD v4.1 allele frequency is therefore below the PALB2 PM2_Supporting threshold of 0.000333%.
PALB2-specific rules support BP1 for this missense variant, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.00 and PVS1, PP3, and BP4 are not applied in this missense setting.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed gnomAD v4.1 allele frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2_Supporting is met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1: absent
- gnomAD v2.1: absent
- PALB2 PM2_Supporting threshold: frequency ≤1/300
- 000 (0.000333%) in gnomAD v4
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for this gene. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- PALB2 VCEP BP1 rule: apply to all missense variants
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%; BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1: absent
- PALB2 BA1 threshold: group maximum filtering allele frequency >0.1%
Sources
BS1 This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%; BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1: absent
- PALB2 BS1 threshold: group maximum filtering allele frequency >0.01%
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar as uncertain significance by a single submitter, but no case-control study data, odds ratio, relative risk, or qualifying statistical enrichment data were identified; PS4 cannot be assessed. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- ClinVar: uncertain significance
- single submitter
- PALB2 PS4 requires case-control evidence with p≤0.05 and effect estimate thresholds
Still missing
- Case-control evidence meeting the PALB2 PS4 statistical thresholds was not identified.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in an affected individual with Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 Supporting/Moderate/Strong/Very Strong requires accumulation of PM3 points.
Evidence considered
- PALB2 PM3 uses a point-based Fanconi anemia framework
Still missing
- Phase information and qualifying recessive case evidence were not identified.
Sources
PP1 No family segregation data or quantitative LOD/Bayes factor evidence were identified to show co-segregation with disease, 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 co-segregation evidence
Still missing
- Segregation data with quantitative LOD score or Bayes factor were not identified.
Sources
BS2 No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2 Supporting/Moderate/Strong requires accumulation of BS2 points.
Evidence considered
- PALB2 BS2 requires point-based evidence from unaffected individuals
Still missing
- Unaffected-observation data or BS2 point assignments were not identified.
Sources
BS4 No segregation study data or quantitative LOD/Bayes factor evidence were identified to show lack of segregation with disease, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor ≤0.053:1 (with lower thresholds for Moderate/Supporting)
Evidence considered
- PALB2 BS4 requires quantitative lack-of-segregation evidence
Still missing
- Segregation data with quantitative LOD score or Bayes factor were not identified.
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution and is not a nonsense, frameshift, or canonical ±1,2 splice variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the PALB2/generic PVS1 scaffold does not support PVS1 for this variant class; PVS1 is not applicable. Details ▾Hide ▴
Rule
Use PALB2 PVS1 decision tree for qualifying loss-of-function or splice-defect variants.
Evidence considered
- PALB2 is PVS1-eligible at the gene level
- Variant-level PVS1 scaffold classifies this variant outside the default null-variant buckets
- SpliceAI max delta score = 0.00
Sources
PS1 N/APS1 is not applicable because the PALB2 VCEP does not use PS1 for missense changes, and no splice-based PS1 evidence was identified for this variant. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table; do not use for missense changes.
Evidence considered
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- SpliceAI max delta score = 0.00
- PALB2 VCEP PS1 instruction: missense do not use
- splicing requires PALB2 PS1 table
Still missing
- No PALB2 PS1 splicing-table match was identified.
Sources
PS2 N/APS2 is not applicable because the PALB2 VCEP does not use de novo evidence under PS2 for PALB2-related disease. Details ▾Hide ▴
PS3 N/APS3 is not applicable in the PALB2 VCEP framework for this variant type, and no qualifying pathogenic functional study evidence was identified for separate use. Details ▾Hide ▴
PM1 N/APM1 is not applicable because the PALB2 VCEP does not use PM1 for PALB2 missense variants. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this variant is not a stop-loss variant, and the PALB2 VCEP does not use PM4 for missense variants. 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
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- PALB2 VCEP PM4 instruction: use for stop-loss variants only
Sources
PM5 N/APM5 is not applicable because the PALB2 VCEP does not use PM5 for missense changes; in PALB2 it is reserved for qualifying truncating or splice variants upstream of p.Tyr1183. Details ▾Hide ▴
Rule
Use as PM5_Supporting for qualifying truncating or splice variants upstream of p.Tyr1183; do not use for missense changes.
Evidence considered
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- PALB2 VCEP PM5 instruction: do not use for missense changes
Sources
PM6 N/APM6 is not applicable because the PALB2 VCEP does not use de novo evidence under PM6 for PALB2-related disease. Details ▾Hide ▴
PP2 N/APP2 is not applicable because the PALB2 VCEP does not use PP2 for PALB2 missense variants. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the PALB2 VCEP does not apply PP3 to missense variants; PP3 is therefore not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via SpliceAI ≥0.2 for qualifying non-canonical splice-relevant variants.
Evidence considered
- SpliceAI max delta score = 0.00
- PALB2 VCEP PP3 instruction: do not use for missense variants
Sources
PP4 N/APP4 is not applicable because the PALB2 VCEP does not use phenotype specificity under PP4 for PALB2-related disease in this setting. Details ▾Hide ▴
PP5 N/APP5 is not used in this VCEP framework, so it is not applicable to this variant. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the PALB2 VCEP framework for this variant type, and no qualifying benign functional study evidence was identified for separate use. Details ▾Hide ▴
BP2 N/ABP2 is not used in the PALB2 VCEP framework for this gene, so it is not applicable to this variant. Details ▾Hide ▴
BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region, and the PALB2 VCEP does not use BP3 for PALB2. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but the PALB2 VCEP does not apply BP4 to missense variants; BP4 is therefore not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.00
- PALB2 VCEP BP4 instruction: do not apply for missense variants
Sources
BP5 N/ABP5 is not applicable because the PALB2 VCEP does not use this criterion for PALB2-related disease. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework, so it is not applicable to this variant. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or qualifying intronic variants, whereas this variant is a missense substitution; BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-supported splice-negative evidence may also be used.
Evidence considered
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- PALB2 VCEP BP7 use is limited to synonymous
- deep intronic
- or RNA-supported splice-negative contexts
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1058A>T
- Protein (HGVS p.)
- NP_078951.2:p.(Lys353Ile)
- GRCh38
- chr16:23635488 T>A
- GRCh37
- chr16:23646809 T>A
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
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 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the PALB2 VCEP does not apply PP3 to missense variants; PP3 is therefore not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via SpliceAI ≥0.2 for qualifying non-canonical splice-relevant variants.
Evidence considered
- SpliceAI max delta score = 0.00
- PALB2 VCEP PP3 instruction: do not use for missense variants
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but the PALB2 VCEP does not apply BP4 to missense variants; BP4 is therefore not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.00
- PALB2 VCEP BP4 instruction: do not apply for missense variants
Sources
BP7 N/ABP7 is intended for synonymous or qualifying intronic variants, whereas this variant is a missense substitution; BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-supported splice-negative evidence may also be used.
Evidence considered
- NM_024675.4:c.1058A>T causes p.(Lys353Ile)
- a missense change
- PALB2 VCEP BP7 use is limited to synonymous
- deep intronic
- or RNA-supported splice-negative contexts
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.086. BayesDel score = -0.4788.
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/3891896/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646809-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635488-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1058…
- OncoKB ↗www.oncokb.org/gene/PALB2/K353I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1058A%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 Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.086. BayesDel score = -0.4788.
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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.