About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.154G>A, p.(Val52Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense variation in PALB2 is considered exceedingly rare relative to truncating disease-causing variants.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.
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
3 / 1,614,050 alleles
gnomAD v4.1: 3 / 1,614,050 alleles. Recorded AF 1.85868e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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: 1 met · 4 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.154G>A (p.Val52Ile) variant has been reported in ClinVar with conflicting single-submitter interpretations of uncertain significance and likely benign.
This variant is absent from gnomAD v2.1 and is present at very low overall frequency in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%), but the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles), which is above the PALB2 PM2 threshold exception and remains below the BS1 and BA1 population thresholds.
SpliceAI predicts no significant splice impact (max delta score 0.01), and REVEL (0.045) and BayesDel (-0.518425) are low; however, the PALB2 VCEP does not use PP3 or BP4 for missense variants, while BP1 is applicable to all PALB2 missense variants.
No criteria match.
Met · 1
BP1 SupportingThis variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense variation in PALB2 is considered exceedingly rare relative to truncating disease-causing variants. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- p.(Val52Ile) missense consequence
- PALB2 VCEP BP1 applies to all missense variants
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Val52Ile), and does not fall into the PALB2 loss-of-function variant categories used for PVS1. Gene-level context supports loss of function as a disease mechanism in PALB2, but this specific change is not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice effect (max delta score 0.01). Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 VCEP PVS1 is reserved for PALB2 loss-of-function/splice-null events
- p.(Val52Ile) missense consequence
- SpliceAI max delta score 0.01
Sources
PM2 This variant is absent from gnomAD v2.1 and is very rare overall in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%). However, the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles) in Remaining individuals, which is above the PALB2 PM2 threshold of 0.000333% and falls under the VCEP exception for a singleton in an under-represented subpopulation, so PM2_Supporting is not applied. Details ▾Hide ▴
Rule
Use as PM2_Supporting when frequency ≤ 1/300,000 (0.000333%) in gnomAD v4; exception for under-represented sub-populations with n=1 but frequency >.0003%
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 0.00019%
- highest subpopulation AF 0.00160% in Remaining individuals
Sources
BA1 Population frequency is well below the PALB2 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 2.8e-07 (0.000028%), which is below the BA1 threshold of 0.1%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 grpmax FAF 2.8e-07
Sources
BS1 Population frequency is below the PALB2 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 2.8e-07 (0.000028%), which is below the BS1 threshold of 0.01%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 grpmax FAF 2.8e-07
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control study or other evidence showing significant enrichment in affected individuals was identified. Available evidence does not support the PALB2 PS4 threshold of p-value 0.05 or less with an odds ratio, hazard ratio, or relative risk of at least 3, or a lower 95% confidence interval of at least 1.5. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤.05 AND (OR/HR/RR ≥3 OR lower 95% CI ≥1.5)
Evidence considered
- ClinVar conflicting single-submitter reports
- No published enrichment data identified
Still missing
- No case-control data or quantified enrichment data were identified for this variant.
Sources
PM3 No evidence was identified that this variant has been observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other qualifying recessive disease context. Available evidence does not support assigning PM3 points. Details ▾Hide ▴
Rule
PM3 point-based scoring for Fanconi anemia context
Evidence considered
- No PM3-qualifying observations identified
Still missing
- No qualifying in trans observations or PM3 point-based evidence were identified.
Sources
PP1 No segregation data were identified for this variant. Available evidence does not support the PALB2 PP1 thresholds based on LOD score, Bayes factor, or affected-relative counts. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 / 0.6 / 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 study or quantitative segregation data were identified.
Sources
BS2 No evidence was identified that this variant has been observed in the number of unaffected individuals required for PALB2 BS2 scoring. Population database observations are not sufficient for this criterion in the PALB2 framework. Details ▾Hide ▴
Rule
BS2 point-based scoring; do not use population based cohorts such as gnomAD
Evidence considered
- PALB2 VCEP states not to use population-based cohorts such as gnomAD for BS2
- No qualifying unaffected-individual data identified
Still missing
- No qualifying unaffected-individual observations or BS2 point-based evidence were identified.
Sources
BS4 No lack-of-segregation data were identified for this variant. Available evidence does not support the PALB2 BS4 thresholds based on LOD score or Bayes factor. Details ▾Hide ▴
Rule
LOD ≤ -1.28 / -0.64 / -0.32 or LR ≤0.053:1 / 0.23 / 0.48
Evidence considered
- No qualifying non-segregation evidence identified
Still missing
- No non-segregation study or quantitative BS4 data were identified.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AAvailable evidence does not support PS1. The PALB2 VCEP does not use PS1 for missense variants, and no evidence was identified that this nucleotide change causes the same pathogenic splicing effect as a previously established pathogenic variant. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: See PALB2 PS1 Table
Evidence considered
- PALB2 VCEP: missense PS1 do not use
- SpliceAI max delta score 0.01
Sources
PS2 N/AThis criterion is not used in the PALB2 VCEP framework for this disorder context. Details ▾Hide ▴
PS3 N/AThis criterion is not used in the PALB2 VCEP framework for this variant type and disease context. Details ▾Hide ▴
PM1 N/AThis criterion is not used for PALB2 because missense pathogenic variation is not an established mechanism of disease in this gene. Details ▾Hide ▴
PM4 N/AThis criterion is not applicable because the PALB2 VCEP uses PM4 only for stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
PM5 N/AThis criterion is not applicable because the PALB2 VCEP does not use PM5 for missense variants. The PALB2-specific PM5 rule is limited to qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183. Details ▾Hide ▴
Rule
Use as PM5_Supporting for qualifying truncating/splice variants; do not use for missense changes
Evidence considered
- p.(Val52Ile) missense consequence
- PALB2 VCEP PM5 missense do not use
Sources
PM6 N/AThis criterion is not used in the PALB2 VCEP framework for this disorder context. Details ▾Hide ▴
PP2 N/AThis criterion is not used for PALB2 because missense variation is not an established disease mechanism for this gene in the PALB2 VCEP framework. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.01), below the PALB2 PP3 splicing threshold of 0.2. REVEL is 0.045 and BayesDel is -0.518425, but the PALB2 VCEP does not use PP3 for missense variants. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.045
- BayesDel -0.518425
- PALB2 VCEP missense PP3 do not use
Sources
PP4 N/AThis criterion is not used for PALB2-related cancer predisposition because the phenotype is not sufficiently specific for a single genetic etiology in the PALB2 VCEP framework. Details ▾Hide ▴
PP5 N/AThis criterion is not for use in the PALB2 VCEP framework. Details ▾Hide ▴
BS3 N/AThis criterion is not used in the PALB2 VCEP framework for this variant type and disease context. Details ▾Hide ▴
BP2 N/AThis criterion is not used in the PALB2 VCEP framework. Details ▾Hide ▴
BP3 N/AThis criterion is not used for PALB2 in the VCEP framework. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL and BayesDel scores are low at 0.045 and -0.518425, respectively. However, the PALB2 VCEP does not apply BP4 to missense variants, even when splice prediction is benign. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≤0.1; do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.045
- BayesDel -0.518425
- PALB2 VCEP missense BP4 do not use
Sources
BP5 N/AThis criterion is not used for PALB2 in the VCEP framework. Details ▾Hide ▴
BP6 N/AThis criterion is not for use in the PALB2 VCEP framework. Details ▾Hide ▴
BP7 N/AThis criterion is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splicing defect in those variant classes. This variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA data
Evidence considered
- p.(Val52Ile) missense consequence
- PALB2 VCEP BP7 variant-class restriction
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.154G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Val52Ile)
- GRCh38
- chr16:23637907 C>T
- GRCh37
- chr16:23649228 C>T
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
3 / 1,614,050 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,050 alleles · 0 hom · FAF 2.8e-07
| Remaining individuals1 / 62,510 | 1.6e-05 |
| European (non-Finnish)2 / 1,179,990 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59974e-05; MAF= 0.00160%, 1/62510 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
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 (max delta score 0.01), below the PALB2 PP3 splicing threshold of 0.2. REVEL is 0.045 and BayesDel is -0.518425, but the PALB2 VCEP does not use PP3 for missense variants. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.045
- BayesDel -0.518425
- PALB2 VCEP missense PP3 do not use
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL and BayesDel scores are low at 0.045 and -0.518425, respectively. However, the PALB2 VCEP does not apply BP4 to missense variants, even when splice prediction is benign. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: SpliceAI ≤0.1; do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.045
- BayesDel -0.518425
- PALB2 VCEP missense BP4 do not use
Sources
BP7 N/AThis criterion is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splicing defect in those variant classes. This variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA data
Evidence considered
- p.(Val52Ile) missense consequence
- PALB2 VCEP BP7 variant-class restriction
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.045. BayesDel score = -0.518425.
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
3 / 1,614,050 recorded alleles
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/231918/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649228-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23637907-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.154G…
- OncoKB ↗www.oncokb.org/gene/PALB2/V52I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.154G%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 1.85868e-06; MAF= 0.00019%, 3/1614050 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59974e-05; MAF= 0.00160%, 1/62510 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.045. BayesDel score = -0.518425.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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.