About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3113G>A, p.(Trp1038Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 1
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change predicted to result in p.(Trp1038Ter)/p.(W1038*). In the PALB2 VCEP framework, loss of function is an established disease mechanism, and the premature termination event occurs well upstream of the final exon-exon junction, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength.
PM5Supporting
PM5 · supporting
This truncating variant creates a premature termination codon at p.(Trp1038Ter), which is upstream of the PALB2 truncation cutoff p.Tyr1183 specified for PM5_Supporting. PM5 is met at supporting strength under the PALB2 VCEP rule.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 1
BS1Strong
BS1 · strong
This variant is present in gnomAD v4 with highest observed population allele frequency 0.0002777778 (0.027778%), which is above the PALB2 BS1 threshold of 0.01%. BS1 is met at strong strength.
Recorded classification: Pathogenic
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, BS1 strong, PM5 supporting, PP5 supporting; maps to Pathogenic.
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
334 / 1,602,804 alleles
gnomAD v4.1: 334 / 1,602,804 alleles. Recorded AF 0.000208385. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
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.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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: 4 met · 2 not met · 6 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 c.3113G>A (p.Trp1038Ter) variant has been reported in ClinVar with a pathogenic expert panel classification and additional pathogenic clinical laboratory submissions.
This variant is present in gnomAD v4 at a total allele frequency of 0.020838% and reaches 0.027778% in the highest observed population, which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.
This variant introduces a premature termination codon and is consistent with a loss-of-function effect in PALB2, a gene for which loss of function is an established disease mechanism in the PALB2 VCEP framework.
SpliceAI predicts splice impact with a maximum delta score of 0.74, but under PALB2-specific rules PP3 is not additionally applied for this nonsense variant type.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a nonsense change predicted to result in p.(Trp1038Ter)/p.(W1038*). In the PALB2 VCEP framework, loss of function is an established disease mechanism, and the premature termination event occurs well upstream of the final exon-exon junction, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; null variant in a gene where loss of function is an established disease mechanism
Evidence considered
- NM_024675.3:c.3113G>A predicts NP_078951.2:p.(Trp1038Ter)/p.(W1038*)
- PALB2 CSPEC includes gene-specific PVS1 guidance
- Gene-level PVS1 gate is marked eligible with loss of function supported
Still missing
- Direct access to the PALB2 exon-map decision-tree worksheet was not available for independent line-by-line confirmation of the branch assignment.
Sources
PM5 SupportingThis truncating variant creates a premature termination codon at p.(Trp1038Ter), which is upstream of the PALB2 truncation cutoff p.Tyr1183 specified for PM5_Supporting. PM5 is met at supporting strength under the PALB2 VCEP rule. Details ▾Hide ▴
Rule
Apply PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183
Evidence considered
- Protein consequence p.(Trp1038Ter)/p.(W1038*)
- PALB2 PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Tyr1183
Sources
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
BS1 StrongThis variant is present in gnomAD v4 with highest observed population allele frequency 0.0002777778 (0.027778%), which is above the PALB2 BS1 threshold of 0.01%. BS1 is met at strong strength. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 highest observed population AF 0.0002777778 in NFE
- PALB2 BS1 threshold >0.01%
Sources
Not met · 2 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4 at a total allele frequency of 0.0002083848 (0.020838%) with highest observed population frequency 0.0002777778 (0.027778%) and therefore is above the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). PM2 is not met. Details ▾Hide ▴
Rule
PM2_Supporting if frequency <=1/300,000 (0.000333%) in gnomAD v4
Evidence considered
- gnomAD v4 total AF 0.0002083848
- gnomAD v4 highest observed population AF 0.0002777778
- PALB2 PM2 threshold <=0.00000333 as proportion (0.000333%)
Sources
BA1 This variant does not meet the PALB2 BA1 threshold. The highest observed population allele frequency in gnomAD v4 is 0.0002777778 (0.027778%), which is below the BA1 threshold of 0.1%. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 highest observed population AF 0.0002777778
- PALB2 BA1 threshold >0.1%
Sources
Not assessed · 6 · no assessment recorded
PS1 PALB2 PS1 relies on a gene-specific splicing table. No reviewed evidence was identified showing that this variant has the same established splice consequence as another PALB2 variant already classified at the required strength. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table
Evidence considered
- PALB2 PS1 requires a gene-specific splicing table
Still missing
- The PALB2 PS1 splicing table was not available for direct variant lookup.
- Variant-matched splice-comparison evidence remains needed if PS1 is being considered.
Sources
PS4 This variant has been reported in ClinVar, including an expert panel pathogenic classification, but no reviewed case-control result meeting the PALB2 PS4 requirement of p-value <=0.05 with an odds ratio, hazard ratio, or relative risk >=3 or lower 95% confidence interval >=1.5 was identified here. Details ▾Hide ▴
Rule
Case-control studies with p-value <=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5
Evidence considered
- ClinVar pathogenic expert panel classification present
- PALB2 PS4 requires qualifying case-control evidence
Still missing
- Variant-specific case-control statistics were not identified.
- Primary literature with exact affected-versus-control counts for this variant remains needed.
Sources
PM3 No reviewed evidence was identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, and no PM3 point total was available. PM3 is not currently assessed. Details ▾Hide ▴
Rule
PM3 strength is assigned from a point total in Fanconi anemia probands
Evidence considered
- PALB2 PM3 requires Fanconi-anemia-specific in trans evidence with a point-based framework
Still missing
- No biallelic Fanconi anemia case evidence was identified.
- Phase-confirmed in trans observations and PM3 point assignment remain needed.
Sources
PP1 No quantitative co-segregation evidence meeting PALB2 PP1 thresholds was identified. Available evidence does not provide a LOD score, Bayes factor, or a documented number of informative segregations sufficient for PP1. Details ▾Hide ▴
Rule
AD condition: LOD >=0.3 or Bayes factor >=2:1 for supporting strength, with higher thresholds for stronger strengths
Evidence considered
- PALB2 PP1 requires quantitative co-segregation assessment
Still missing
- No pedigree-based LOD or Bayes factor was identified.
- Variant-specific segregation counts in affected relatives remain needed.
Sources
BS2 No reviewed evidence was identified showing this variant in healthy adults or in unaffected individuals meeting PALB2 BS2 point-based thresholds. Population database observations alone are not sufficient for BS2 in this framework. Details ▾Hide ▴
Rule
BS2 strength is assigned from a point total in qualifying unaffected individuals
Evidence considered
- PALB2 BS2 does not use population database observations such as gnomAD
Still missing
- No qualifying unaffected-carrier evidence was identified.
- Fanconi-anemia-specific BS2 point assignment remains unavailable.
Sources
BS4 No quantitative non-segregation evidence meeting PALB2 BS4 thresholds was identified. Available evidence does not show a LOD score or Bayes factor supporting lack of segregation with disease. Details ▾Hide ▴
Rule
LOD <=-0.32 or Bayes factor <=0.48:1 for supporting strength, with lower thresholds for stronger strengths
Evidence considered
- PALB2 BS4 requires quantitative non-segregation assessment
Still missing
- No pedigree-based non-segregation analysis was identified.
- Variant-specific unaffected-carrier and non-segregation data remain needed.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APALB2 PS2 is not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 PS2 marked not applicable
Sources
PS3 N/APALB2 PS3 is not applicable in this framework for this variant assessment. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 PS3 marked not applicable
- Curated literature context suggests loss of function
- but no qualifying PS3 framework use was identified
Sources
PM1 N/APALB2 PM1 is not applicable in this framework. No hotspot-based rule applies for this variant. Details ▾Hide ▴
Rule
Do not use for PALB2
Evidence considered
- PALB2 PM1 is marked not applicable
- Cancer Hotspots did not identify a statistically significant hotspot
Sources
PM4 N/APALB2 PM4 is reserved for stop-loss variants in this framework and does not apply to this nonsense variant. Details ▾Hide ▴
Rule
Use for stop-loss variants only
Evidence considered
- Variant type is nonsense
- not stop-loss
Sources
PM6 N/APALB2 PM6 is not applicable in this framework. Details ▾Hide ▴
Rule
Do not use for AD or AR disease in this framework
Evidence considered
- PALB2 PM6 marked not applicable
Sources
PP2 N/APALB2 PP2 is not applicable in this framework. Details ▾Hide ▴
PP3 N/ASpliceAI predicts possible splice impact with a maximum delta score of 0.74, but the PALB2 PP3 rule is specified for silent, missense/in-frame, and relevant non-canonical intronic variants rather than this nonsense variant. PP3 is therefore not applied. Details ▾Hide ▴
Rule
PP3 applies to predicted splice impact for silent, missense/in-frame, and relevant non-canonical intronic variants
Evidence considered
- SpliceAI max delta score 0.74
- PALB2 PP3 rule scope excludes this nonsense variant type
Sources
PP4 N/APALB2 PP4 is not used for the autosomal dominant cancer-predisposition setting in this framework because the phenotype is not sufficiently specific. Details ▾Hide ▴
Rule
Do not use for AD PALB2-related cancer predisposition
Evidence considered
- PALB2 PP4 marked not applicable for AD disorder
Sources
BS3 N/APALB2 BS3 is not applicable in this framework for this variant assessment. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 BS3 marked not applicable
Sources
BP1 N/AThis is not a missense variant. PALB2 BP1 applies to missense variants only. Details ▾Hide ▴
BP2 N/APALB2 BP2 is not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 BP2 marked not applicable
Sources
BP3 N/APALB2 BP3 is not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 BP3 marked not applicable
Sources
BP4 N/ABP4 is not applicable because this is not a missense variant, and splicing prediction does not show a low-impact result. SpliceAI shows a maximum delta score of 0.74, which is above the PALB2 BP4 threshold of <=0.1. Details ▾Hide ▴
Rule
BP4 applies only when no predicted splicing impact is present (SpliceAI <=0.1) and is not used here
Evidence considered
- SpliceAI max delta score 0.74
- PALB2 BP4 splicing threshold <=0.1
Sources
BP5 N/APALB2 BP5 is not applicable in this framework. Details ▾Hide ▴
BP6 N/APALB2 BP6 is not applicable for this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP framework
Evidence considered
- PALB2 BP6 marked not applicable for this VCEP
Sources
BP7 N/AThis is not a synonymous or deep intronic variant, so PALB2 BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous and deep intronic variants, with optional RNA-based extensions
Evidence considered
- Variant type is nonsense
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.3113G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Trp1038Ter)
- GRCh38
- chr16:23621362 C>T
- GRCh37
- chr16:23632683 C>T
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
334 / 1,602,804 alleles
AF 0.000208 · 0 homozygotes · FAF 0.000252
gnomAD v2.1
17 / 282,756 alleles
AF 6.01e-05 · 0 homozygotes · FAF 6.66e-05
By genetic ancestry
gnomAD v4.1
AF 0.00021 · 334 / 1,602,804 alleles · 0 hom · FAF 0.00025
| European (non-Finnish)325 / 1,170,000 | 0.00028 |
| African/African American5 / 74,618 | 6.7e-05 |
| Remaining individuals4 / 62,120 | 6.4e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 6e-05 · 17 / 282,756 alleles · 0 hom · FAF 6.7e-05
| African/African American3 / 24,968 | 0.00012 |
| European (non-Finnish)14 / 129,120 | 0.00011 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts possible splice impact with a maximum delta score of 0.74, but the PALB2 PP3 rule is specified for silent, missense/in-frame, and relevant non-canonical intronic variants rather than this nonsense variant. PP3 is therefore not applied. Details ▾Hide ▴
Rule
PP3 applies to predicted splice impact for silent, missense/in-frame, and relevant non-canonical intronic variants
Evidence considered
- SpliceAI max delta score 0.74
- PALB2 PP3 rule scope excludes this nonsense variant type
Sources
BP4 N/ABP4 is not applicable because this is not a missense variant, and splicing prediction does not show a low-impact result. SpliceAI shows a maximum delta score of 0.74, which is above the PALB2 BP4 threshold of <=0.1. Details ▾Hide ▴
Rule
BP4 applies only when no predicted splicing impact is present (SpliceAI <=0.1) and is not used here
Evidence considered
- SpliceAI max delta score 0.74
- PALB2 BP4 splicing threshold <=0.1
Sources
BP7 N/AThis is not a synonymous or deep intronic variant, so PALB2 BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous and deep intronic variants, with optional RNA-based extensions
Evidence considered
- Variant type is nonsense
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.74). 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
334 / 1,602,804 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/126711/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23632683-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23621362-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.3113…
- OncoKB ↗www.oncokb.org/gene/PALB2/W1038*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107875192
- 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= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.74). BayesDel score = 0.63.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104552889, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.