About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1432T>C, p.(Ser478Pro)
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, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). The variant is also absent from gnomAD v2.1.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 specification applies BP1_Supporting to all missense variants because pathogenic PALB2 disease is predominantly associated with truncating variants and true pathogenic missense variants are thought to be exceedingly rare.
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: PM2 supporting, BP1 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 · 3 not met · 5 not assessed · 18 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.1432T>C (p.Ser478Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with conflicting germline submissions, including uncertain significance and likely benign interpretations.
This variant is absent from gnomAD v2.1 and gnomAD v4.1; the observed frequency is therefore below the PALB2 PM2_Supporting threshold of ≤0.000333% and below the benign population thresholds for BS1 and BA1.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 splice thresholds used for PP3 (≥0.2) and BP4 (≤0.1), although PP3 and BP4 are not applied to missense variants under the PALB2 specification.
Under the PALB2 expert specification, BP1_Supporting is met because this is a missense variant in a gene where disease is primarily associated with truncating variants, while PVS1 is not met because this variant is not a qualifying loss-of-function change.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). The variant is also absent from gnomAD v2.1. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 absent
- gnomAD v2.1 absent
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 specification applies BP1_Supporting to all missense variants because pathogenic PALB2 disease is predominantly associated with truncating variants and true pathogenic missense variants are thought to be exceedingly rare. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant protein change p.(Ser478Pro) is missense
- PALB2 BP1 applies to all missense variants
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function categories used for PVS1. The variant-level assessment states that c.1432T>C is not a nonsense, frameshift, or canonical ±1/2 splice-site variant, so PVS1 is not applied. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 VCEP framework includes PVS1 for loss-of-function variants
- pvs1_variant_assessment bucketed this variant as 'other' rather than a null variant
Sources
BA1 This variant is absent from gnomAD v4.1, so the observed population 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
Sources
BS1 This variant is absent from gnomAD v4.1, so the observed population 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
Sources
Not assessed · 5 · no assessment recorded
PS4 Available evidence does not show a PALB2 case-control study for this variant meeting the PS4 threshold of p≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. ClinVar submissions alone do not satisfy this requirement. 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 reports 2 uncertain significance submissions and 1 likely benign submission
- No case-control statistics were identified
Still missing
- No qualifying PALB2 case-control data for this variant were identified.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia, so PM3 cannot be evaluated. Details ▾Hide ▴
Rule
PM3 point-based Fanconi anemia framework
Evidence considered
- No PM3-eligible proband data identified
Still missing
- No phase-confirmed Fanconi anemia observations were identified.
Sources
PP1 No segregation data were identified for this variant, so the PALB2 quantitative co-segregation thresholds for PP1 were not met or evaluated. Details ▾Hide ▴
Rule
AD condition: LOD ≥0.3 / 0.60 / 1.26 or Bayes factor ≥2:1 / 4:1 / 18:1 for supporting / moderate / strong
Evidence considered
- No PP1-eligible segregation data identified
Still missing
- No family segregation or likelihood ratio data were identified.
Sources
BS2 No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be evaluated. Details ▾Hide ▴
Rule
BS2 point-based Fanconi anemia framework
Evidence considered
- No BS2-eligible observations identified
Still missing
- No qualifying unaffected-observation data were identified.
Sources
BS4 No quantitative segregation data were identified showing lack of segregation for this variant, so BS4 cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -1.28 / -0.64 / -0.32 or Bayes factor ≤0.053:1 / 0.23 / 0.48 for strong / moderate / supporting
Evidence considered
- No BS4-eligible family data identified
Still missing
- No family-based lack-of-segregation data or LOD/Bayes factor calculations were identified.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThe PALB2 specification does not use PS1 for missense changes. PS1 is reserved for splice-based equivalence using the PALB2 PS1 splicing table, and no such splice evidence was identified for this missense variant. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: See PALB2 PS1 Table
Evidence considered
- PALB2 PS1 instructions: missense do not use
- SpliceAI max delta score 0.01
Sources
PS2 N/AThe PALB2 specification does not use PS2 for this gene-disease context. No informative confirmed de novo evidence is used for PALB2-related cancer predisposition in this framework. Details ▾Hide ▴
PS3 N/AThe PALB2 specification does not apply PS3 for this variant type in this framework. No PALB2 protein functional study meeting an applicable PS3 rule was identified. Details ▾Hide ▴
PM1 N/AThe PALB2 specification does not use PM1 because missense pathogenic variation is not yet established as a disease mechanism in PALB2. This variant is therefore not evaluated under PM1. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this variant is a missense substitution and not a stop-loss variant or qualifying in-frame length-changing variant under the PALB2 specification. Details ▾Hide ▴
PM5 N/AThe PALB2 specification limits PM5 to truncating or certain splice variants and states that missense changes should not use PM5. This missense variant therefore does not qualify. Details ▾Hide ▴
Rule
Use as PM5_Supporting only for qualifying truncating or splice variants upstream of p.Tyr1183*
Evidence considered
- PALB2 PM5 instructions: do not use for missense changes
Sources
PM6 N/AThe PALB2 specification does not use PM6 for this gene-disease context. No assumed de novo evidence is used in this framework. Details ▾Hide ▴
PP2 N/AThe PALB2 specification does not use PP2 because missense variation is not established as a common pathogenic mechanism in PALB2. Details ▾Hide ▴
PP3 N/AThe PALB2 specification does not use PP3 for missense variants. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, the PP3 splice threshold is ≥0.2 and missense variants are excluded from PP3 use in this framework. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 PP3 instructions: missense do not use
Sources
PP4 N/AThe PALB2 specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for a single genetic cause. Details ▾Hide ▴
PP5 N/APP5 is not used by this VCEP. External assertions without independently reviewable evidence are not applied in the PALB2 specification. Details ▾Hide ▴
BS3 N/AThe PALB2 specification does not apply BS3 for this variant type in this framework. No applicable benign functional study rule was identified. Details ▾Hide ▴
BP2 N/AThe PALB2 specification does not use BP2 in this framework. 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 specification does not use BP3 for this context. Details ▾Hide ▴
BP4 N/AAlthough SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the PALB2 BP4 splice threshold of ≤0.1, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 instructions: do not apply for missense variants
Sources
BP5 N/AThe PALB2 specification does not use BP5 for this gene-disease context. Details ▾Hide ▴
BP6 N/ABP6 is not used by this VCEP. External benign assertions without independently reviewable evidence are not applied in the PALB2 specification. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splice defect in those contexts. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA evidence
Evidence considered
- Variant is missense
- not synonymous or deep intronic
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1432T>C
- Protein (HGVS p.)
- NP_078951.2:p.(Ser478Pro)
- GRCh38
- chr16:23635114 A>G
- GRCh37
- chr16:23646435 A>G
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/AThe PALB2 specification does not use PP3 for missense variants. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, the PP3 splice threshold is ≥0.2 and missense variants are excluded from PP3 use in this framework. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 PP3 instructions: missense do not use
Sources
BP4 N/AAlthough SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the PALB2 BP4 splice threshold of ≤0.1, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applied. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 instructions: do not apply for missense variants
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splice defect in those contexts. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA evidence
Evidence considered
- Variant is missense
- not synonymous or deep intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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/642825/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646435-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635114-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1432…
- OncoKB ↗www.oncokb.org/gene/PALB2/S478P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1432T%3EC
- 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 (2 clinical laboratories) and as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.