About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.968C>T, p.(Ala323Val)
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 population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of ≤1/300,000 (0.000333%), so PM2_Supporting is met.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and PALB2 specifications apply BP1 to all missense variants because pathogenic missense variation is considered very uncommon in this gene. Therefore BP1 is met at Supporting strength.
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 · 7 not met · 5 not assessed · 14 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.968C>T (p.Ala323Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PALB2 PM2_Supporting threshold of 0.000333%.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splice threshold of 0.2.
As a missense variant in PALB2, this change meets BP1 because pathogenic missense variation is considered uncommon in this gene under the PALB2 specifications.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is therefore 0, which is 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
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- PALB2 PM2 is applied only at Supporting strength
Sources
BP1 SupportingThis variant is a missense substitution, and PALB2 specifications apply BP1 to all missense variants because pathogenic missense variation is considered very uncommon in this gene. Therefore BP1 is met at Supporting strength. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant is missense p.(Ala323Val)
- PALB2 BP1 applies to all missense variants
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function PVS1 categories, and the generic PVS1 scaffold states that it is not a nonsense, frameshift, or canonical ±1,2 splice variant. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.03, so PVS1 is not met. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2-specific PVS1 framework is available and loss of function is an established disease mechanism for PALB2
- Variant is a missense change p.(Ala323Val)
- Generic PVS1 scaffold does not place this variant in a default null-variant bucket
- SpliceAI max delta score 0.03
Sources
PS1 Available evidence does not support PS1. PALB2 PS1 is not used for missense changes, and no evidence was identified that this variant matches a qualifying PALB2 splicing-table entry. Details ▾Hide ▴
Rule
Missense: do not use; splicing: use PALB2 PS1 table
Evidence considered
- Variant is missense p.(Ala323Val)
- PALB2 VCEP states PS1 should not be used for missense changes
- SpliceAI max delta score 0.03 does not suggest a qualifying splice effect
Sources
PM5 Available evidence does not support PM5. PALB2 applies PM5 only to truncating variants with premature termination codons upstream of p.Tyr1183 or to qualifying splice variants with observed RNA evidence, and this variant is neither. Details ▾Hide ▴
Rule
Apply only to qualifying truncating or splice variants as PM5_Supporting
Evidence considered
- Variant is missense p.(Ala323Val)
- SpliceAI max delta score 0.03 does not support a qualifying splice effect
Sources
PP3 Available evidence does not support PP3. For PALB2, PP3 is not used for missense prediction, and splice-based PP3 requires SpliceAI ≥0.2; this variant has a maximum SpliceAI delta score of 0.03, which is below that threshold. Details ▾Hide ▴
Rule
Missense: do not use; splicing: SpliceAI ≥0.2
Evidence considered
- Variant is missense p.(Ala323Val)
- SpliceAI max delta score 0.03
- PALB2 PP3 splice threshold is ≥0.2
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
Evidence considered
- Absent from gnomAD v4.1
- PALB2 BA1 threshold is >0.1%
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
Evidence considered
- Absent from gnomAD v4.1
- PALB2 BS1 threshold is >0.01%
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, which is at or below the PALB2 BP4 splice threshold of ≤0.1. However, PALB2 specifications state that BP4 should not be applied for missense variants, so BP4 is not met. Details ▾Hide ▴
Rule
Missense: do not use; splicing: SpliceAI ≤0.1
Evidence considered
- Variant is missense p.(Ala323Val)
- SpliceAI max delta score 0.03
- PALB2 BP4 splice threshold is ≤0.1 but criterion is not applied for missense variants
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar as uncertain significance, but no case-control study was identified showing a significant enrichment in affected individuals with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. Therefore PS4 is not currently 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 reports uncertain significance with 6 clinical laboratory submissions
- No qualifying case-control statistics identified for this variant
Still missing
- No qualifying PALB2 case-control data for this specific variant were identified.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Fanconi anemia point-based PM3 framework
Evidence considered
- No qualifying PM3 proband or phase data identified
Still missing
- No phase-confirmed Fanconi anemia proband data were identified for this variant.
Sources
PP1 No quantitative segregation data were identified for this variant, so the PALB2 LOD-score or Bayes factor thresholds for PP1 cannot be evaluated. Details ▾Hide ▴
Rule
AD: LOD ≥0.3/0.60/1.26 or LR ≥2:1/4:1/18:1; AR: segregation in 1/2/≥3 affected relatives
Evidence considered
- No qualifying segregation evidence identified
Still missing
- No family segregation data or calculated LOD/Bayes factor were identified.
Sources
BS2 No data were identified showing this variant in healthy individuals meeting the PALB2 Fanconi anemia BS2 point-based framework, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Fanconi anemia point-based BS2 framework
Evidence considered
- No qualifying BS2 point-based observations identified
Still missing
- No qualifying BS2 healthy-observation dataset was identified for this variant.
Sources
BS4 No quantitative non-segregation data were identified for this variant, so the PALB2 BS4 LOD-score or Bayes factor thresholds cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -0.32/-0.64/-1.28 or LR ≤0.48/0.23/0.053:1
Evidence considered
- No qualifying BS4 segregation data identified
Still missing
- No family non-segregation data or calculated LOD/Bayes factor were identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APALB2 specifications state that PS2 should not be used for this gene-disease setting, and no informative confirmed de novo evidence was identified. Details ▾Hide ▴
PS3 N/APALB2 specifications do not use PS3 for this setting. No well-established functional evidence was identified that would override the gene-specific rule. Details ▾Hide ▴
PM1 N/APALB2 specifications state that PM1 should not be used because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. Details ▾Hide ▴
PM4 N/AThis is a missense substitution, not a stop-loss variant, and PALB2 specifications state that PM4 is not applicable for in-frame changes less than a single exon. Details ▾Hide ▴
Evidence considered
- Variant is missense p.(Ala323Val)
- PALB2 PM4 is reserved for stop-loss variants
Sources
PM6 N/APALB2 specifications state that PM6 should not be used for this gene-disease setting, and no assumed de novo evidence was identified. Details ▾Hide ▴
PP2 N/APALB2 specifications state that PP2 should not be used because missense variation is not an established disease mechanism for PALB2. Details ▾Hide ▴
PP4 N/APALB2 specifications state that PP4 should not be used for the autosomal dominant cancer predisposition setting because the phenotype is genetically heterogeneous and not sufficiently specific. Details ▾Hide ▴
PP5 N/APALB2 specifications state that PP5 is not for use in this VCEP framework. Details ▾Hide ▴
BS3 N/APALB2 specifications do not use BS3 for this setting. No well-established functional evidence was identified that would support a benign functional code under the PALB2 framework. Details ▾Hide ▴
BP2 N/APALB2 specifications mark BP2 as not applicable, and no qualifying cis/trans observation framework was identified for use here. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion, and PALB2 specifications state that BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense p.(Ala323Val)
- PALB2 VCEP marks BP3 not applicable
Sources
BP5 N/APALB2 specifications state that BP5 should not be used for this gene because co-occurrence with other pathogenic variants does not provide reliable benign evidence in this setting. Details ▾Hide ▴
BP6 N/APALB2 specifications state that BP6 is not for use in this VCEP framework. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, and no RNA study showing lack of aberrant splicing was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous/deep intronic variants or RNA evidence showing no aberrant defect
Evidence considered
- Variant is missense p.(Ala323Val)
- No RNA evidence identified
- SpliceAI max delta score 0.03
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.968C>T
- Protein (HGVS p.)
- NP_078951.2:p.(Ala323Val)
- GRCh38
- chr16:23635578 G>A
- GRCh37
- chr16:23646899 G>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 Available evidence does not support PP3. For PALB2, PP3 is not used for missense prediction, and splice-based PP3 requires SpliceAI ≥0.2; this variant has a maximum SpliceAI delta score of 0.03, which is below that threshold. Details ▾Hide ▴
Rule
Missense: do not use; splicing: SpliceAI ≥0.2
Evidence considered
- Variant is missense p.(Ala323Val)
- SpliceAI max delta score 0.03
- PALB2 PP3 splice threshold is ≥0.2
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, which is at or below the PALB2 BP4 splice threshold of ≤0.1. However, PALB2 specifications state that BP4 should not be applied for missense variants, so BP4 is not met. Details ▾Hide ▴
Rule
Missense: do not use; splicing: SpliceAI ≤0.1
Evidence considered
- Variant is missense p.(Ala323Val)
- SpliceAI max delta score 0.03
- PALB2 BP4 splice threshold is ≤0.1 but criterion is not applied for missense variants
Sources
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, and no RNA study showing lack of aberrant splicing was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous/deep intronic variants or RNA evidence showing no aberrant defect
Evidence considered
- Variant is missense p.(Ala323Val)
- No RNA evidence identified
- SpliceAI max delta score 0.03
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.061. BayesDel score = -0.514065.
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/482023/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646899-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635578-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.968C…
- OncoKB ↗www.oncokb.org/gene/PALB2/A323V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.968C%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 (6 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.061. BayesDel score = -0.514065.
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.