About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.49-2A>T, p.?
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (AF 0.00006%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). This supports PM2 at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 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
1 / 1,613,414 alleles
gnomAD v4.1: 1 / 1,613,414 alleles. Recorded AF 6.19804e-07. Recorded homozygote count 0.
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 ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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 · 2 not met · 9 not assessed · 16 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 NM_024675.3:c.49-2A>T (NP_078951.2:p.?) variant has been reported in ClinVar, where submissions include likely pathogenic and uncertain significance interpretations, and the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel has classified it as uncertain significance.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 population thresholds.
This variant affects a canonical splice acceptor position in a gene for which loss of function is an established disease mechanism, but the exact transcript consequence for this variant remains unresolved in the available evidence.
Available computational evidence is mixed: SpliceAI shows a max delta score of 0.00, whereas BayesDel is 0.63, and these data do not independently resolve the splice consequence for this canonical splice-site variant.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (AF 0.00006%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v2.1
- Present once in gnomAD v4.1 with total AF 6.198037205577738e-07
Sources
Not met · 2 · evaluated, threshold not reached
BA1 The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BA1 threshold of >0.1%. BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 best subpopulation AF 8.479088871026275e-07
Sources
BS1 The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BS1 threshold of >0.01%. BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 best subpopulation AF 8.479088871026275e-07
Sources
Not assessed · 9 · no assessment recorded
PVS1 This variant affects the canonical -2 splice acceptor position in PALB2, and loss of function is an established disease mechanism for this gene. However, the available materials do not include the PALB2 exon-specific PVS1 decision-tree outcome or direct RNA evidence for this exact variant, and SpliceAI shows a max delta score of 0.00, so PVS1 is left for manual review rather than applied automatically. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- Canonical splice acceptor variant at c.49-2
- PALB2 CSPEC includes PVS1 guidance
- PALB2 loss of function is an established disease mechanism
- SpliceAI max delta score 0.00
- ClinVar expert panel classification is VUS
Still missing
- Direct application of the PALB2-specific PVS1 decision tree for this splice junction was not available.
- No RNA study for this exact variant was identified to confirm the transcript consequence.
- The effect on exon usage
- reading frame
- and NMD remains to be confirmed for this exact variant.
Sources
PS1 The PALB2 specification indicates that PS1 for splice variants requires the PALB2 PS1 splicing table. No table-based match or equivalent previously established splice event was identified for this variant. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- PALB2 PS1 requires the panel splicing table
Still missing
- No PALB2 PS1 splicing-table match was identified for this variant.
Sources
PS4 This variant has been reported in ClinVar, but no case-control study or other enrichment analysis was identified showing a statistically significant excess in affected individuals. The available evidence does not establish the PALB2 PS4 threshold. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- ClinVar submissions exist for this variant
- No qualifying case-control evidence identified
Still missing
- No odds ratio
- relative risk
- or lower 95% confidence interval meeting the PALB2 PS4 rule was identified.
- No variant-specific case-control dataset was identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assigned. Details ▾Hide ▴
Rule
See Fanconi Anemia PM3 tables for approach to assign points per proband.
Evidence considered
- PALB2 PM3 requires Fanconi anemia point-based evidence
Still missing
- No phase-confirmed recessive observations were identified.
- No PM3 point-based evidence was identified.
Sources
PM5 The PALB2 specification allows PM5_Supporting for selected truncating or splice variants only when the required RNA-based and NMD-prone conditions are met. Those variant-specific prerequisites were not established here. Details ▾Hide ▴
Rule
Apply to splice variants as with premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone.
Evidence considered
- PALB2 PM5 for splice variants requires RNA-based PVS1_VS and NMD-prone consequence
Still missing
- No evidence was identified that this exact splice variant meets the PALB2 PM5 splice prerequisites.
- No qualifying RNA result was identified.
Sources
PP1 No segregation data were identified for this variant, so the PALB2 PP1 thresholds were not met. Details ▾Hide ▴
Rule
AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1 for supporting strength, with higher thresholds for moderate and strong.
Evidence considered
- ClinVar record available without usable segregation evidence
Still missing
- No LOD score or Bayes factor was identified.
- No affected-relative segregation data were identified.
Sources
BS2 No qualifying observations in healthy individuals were identified that would allow PALB2 BS2 point assignment. Details ▾Hide ▴
Rule
See Fanconi Anemia BS2 tables for approach to assign points per proband.
Evidence considered
- PALB2 BS2 requires point-based healthy-individual evidence
Still missing
- No BS2 point-based observations were identified.
Sources
BS4 No non-segregation evidence was identified for this variant, so the PALB2 BS4 thresholds were not met. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 for strong strength, with lower thresholds for moderate and supporting.
Evidence considered
- ClinVar record available without usable non-segregation evidence
Still missing
- No LOD score or Bayes factor supporting non-segregation was identified.
- No family data documenting lack of segregation were identified.
Sources
BP4 SpliceAI shows no predicted splice impact for this variant (max delta score 0.00), which meets the PALB2 BP4 numeric threshold of ≤0.1. However, this is a canonical -2 splice acceptor variant that is primarily evaluated under the PALB2 PVS1 framework, and the available evidence does not establish that BP4 should be used to counter a canonical splice-site interpretation here. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
- SpliceAI max delta score 0.00
- Variant is at canonical -2 splice position
Still missing
- Clarification is needed on whether PALB2 BP4 should be applied to this canonical ±1
- 2 splice-site variant.
- No direct RNA evidence was identified to confirm a benign splice outcome.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo evidence is not used for PALB2 in this specification. Details ▾Hide ▴
PS3 N/APS3 is not applicable for PALB2 in this specification. No well-established functional study for this exact variant was provided that would override the panel rule. Details ▾Hide ▴
Evidence considered
- PALB2 CSPEC marks PS3 not applicable
Sources
PM1 N/APM1 is not applicable for PALB2 because missense pathogenic variation has not been established as a disease mechanism in this specification, and this is not a mutational hot-spot criterion for the current variant type. Details ▾Hide ▴
PM4 N/APM4 is not applicable for PALB2 except for stop-loss variants, and this variant is a splice-site change. Details ▾Hide ▴
PM6 N/APM6 is not used for PALB2 in this specification. Details ▾Hide ▴
PP2 N/APP2 is not applicable for PALB2 in this specification. Details ▾Hide ▴
PP3 N/AFor PALB2, PP3 for splicing is limited to silent, missense, in-frame, and intronic variants outside the donor and acceptor ±1,2 positions. This variant is a canonical -2 splice-site change, so PP3 is not applied. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
- Variant is at canonical -2 position
- PALB2 PP3 rule excludes donor/acceptor 1
- 2 variants
- Generic PVS1 scaffold advises against double-counting splice prediction evidence
Sources
PP4 N/APP4 is not applicable for PALB2-related autosomal dominant cancer predisposition in this specification. Details ▾Hide ▴
PP5 N/APP5 is not applicable and is not used for variant interpretation in this specification. Details ▾Hide ▴
BS3 N/ABS3 is not applicable for PALB2 in this specification, and no well-established study showing a normal effect for this exact variant was provided. Details ▾Hide ▴
Evidence considered
- PALB2 CSPEC marks BS3 not applicable
Sources
BP1 N/ABP1 applies to missense variants in PALB2. This variant is a splice-site change, so BP1 is not applicable. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- PALB2 BP1 applies to missense variants only
Sources
BP2 N/ABP2 is not applicable for PALB2 in this specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable for PALB2 in this specification. Details ▾Hide ▴
BP5 N/ABP5 is not applicable for PALB2 in this specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable and is not used for PALB2 variant interpretation in this specification. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous and deep intronic variants or for RNA evidence showing no aberrant splicing. This canonical -2 splice-site variant does not meet that use case, and no RNA study showing a normal splice outcome was identified. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or for observed lack of aberrant RNA defect in qualifying assays.
Evidence considered
- Variant is not synonymous or deep intronic
- No benign RNA result identified
Still missing
- No RNA study showing a normal splice outcome was identified.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.49-2A>T
- Protein (HGVS p.)
- NP_078951.2:p.?
- GRCh38
- chr16:23638131 T>A
- GRCh37
- chr16:23649452 T>A
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
1 / 1,613,414 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,414 alleles · 0 hom
| European (non-Finnish)1 / 1,179,372 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, 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= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47909e-07; MAF= 0.00008%, 1/1179372 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SpliceAI shows no predicted splice impact for this variant (max delta score 0.00), which meets the PALB2 BP4 numeric threshold of ≤0.1. However, this is a canonical -2 splice acceptor variant that is primarily evaluated under the PALB2 PVS1 framework, and the available evidence does not establish that BP4 should be used to counter a canonical splice-site interpretation here. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
- SpliceAI max delta score 0.00
- Variant is at canonical -2 splice position
Still missing
- Clarification is needed on whether PALB2 BP4 should be applied to this canonical ±1
- 2 splice-site variant.
- No direct RNA evidence was identified to confirm a benign splice outcome.
Sources
PP3 N/AFor PALB2, PP3 for splicing is limited to silent, missense, in-frame, and intronic variants outside the donor and acceptor ±1,2 positions. This variant is a canonical -2 splice-site change, so PP3 is not applied. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
- Variant is at canonical -2 position
- PALB2 PP3 rule excludes donor/acceptor 1
- 2 variants
- Generic PVS1 scaffold advises against double-counting splice prediction evidence
Sources
BP7 N/ABP7 is intended for synonymous and deep intronic variants or for RNA evidence showing no aberrant splicing. This canonical -2 splice-site variant does not meet that use case, and no RNA study showing a normal splice outcome was identified. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or for observed lack of aberrant RNA defect in qualifying assays.
Evidence considered
- Variant is not synonymous or deep intronic
- No benign RNA result identified
Still missing
- No RNA study showing a normal splice outcome was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.63.
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
1 / 1,613,414 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 ↗
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/186820/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649452-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23638131-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.49-2…
- OncoKB ↗www.oncokb.org/gene/PALB2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.49-2A%3ET
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= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47909e-07; MAF= 0.00008%, 1/1179372 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance 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 = 0.00). BayesDel score = 0.63.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).