About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3362del, p.(Gly1121ValfsTer3)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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: 0
Pathogenic criteria applied · 3
PVS1Strong
PVS1 · strong
This variant is a frameshift predicted to truncate PALB2 as p.(Gly1121ValfsTer3) / p.(G1121Vfs*3). Germline loss of function is an established disease mechanism for PALB2, and the PALB2 specification directs use of a gene-specific PVS1 decision tree. Because this is a distal truncating event and the PALB2 specification separately treats truncating variants upstream of p.Tyr1183 as clinically relevant, PVS1 is applied with downgrade from Very Strong to Strong pending exact confirmation of the PALB2 decision-tree node for this late truncation.
PM5Supporting
PM5 · supporting
The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift is predicted as p.(Gly1121ValfsTer3), which truncates the protein upstream of p.Tyr1183, so PM5_Supporting is met.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 strong, PP5 supporting, PM5 supporting; maps to Likely 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
13 / 1,613,660 alleles
gnomAD v4.1: 13 / 1,613,660 alleles. Recorded AF 8.05622e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79863e-06; MAF= 0.00088%, 1/113654 alleles, homozygotes = 0).
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.
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: 3 met · 4 not met · 5 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.3362del (NP_078951.2:p.(Gly1121ValfsTer3), p.(G1121Vfs*3)) variant has been reported in ClinVar, including an expert panel likely pathogenic classification and multiple pathogenic or likely pathogenic clinical laboratory submissions.
In gnomAD v4.1, this variant is present at 13/1,613,660 alleles (AF 0.00081%) with highest observed frequency 0.00134% in African/African American individuals; this is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2_Supporting threshold.
Published evidence supports PALB2 as a tumor suppressor gene in which truncating variants are disease-relevant, and this frameshift is predicted to truncate the protein upstream of the PALB2 p.Tyr1183 truncation boundary used for PM5_Supporting.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
No criteria match.
Met · 3
PVS1 StrongThis variant is a frameshift predicted to truncate PALB2 as p.(Gly1121ValfsTer3) / p.(G1121Vfs*3). Germline loss of function is an established disease mechanism for PALB2, and the PALB2 specification directs use of a gene-specific PVS1 decision tree. Because this is a distal truncating event and the PALB2 specification separately treats truncating variants upstream of p.Tyr1183 as clinically relevant, PVS1 is applied with downgrade from Very Strong to Strong pending exact confirmation of the PALB2 decision-tree node for this late truncation. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- Frameshift consequence p.(Gly1121ValfsTer3) / p.(G1121Vfs*3).
- PALB2 has established loss-of-function disease mechanism.
- PALB2 specification uses a gene-specific PVS1 decision tree for truncating variants.
Still missing
- Exact PALB2 decision-tree node for this distal truncating event was not independently viewable in the retrieved materials.
- RNA or protein-level confirmation for this specific variant was not identified.
Sources
PM5 SupportingThe PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift is predicted as p.(Gly1121ValfsTer3), which truncates the protein upstream of p.Tyr1183, so PM5_Supporting is met. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183
Evidence considered
- Predicted protein consequence p.(Gly1121ValfsTer3) / p.(G1121Vfs*3).
- PALB2 PM5_Supporting rule for truncating variants upstream of p.Tyr1183.
Sources
cspec ↗pvs1_variant_assessment
Not met · 4 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 at 13/1,613,660 alleles (AF 0.00081%), with highest observed frequency 0.00134% in African/African American individuals. These values are above the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2 is not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset; use as PM2_Supporting
Evidence considered
- gnomAD v4.1 total AF 8.05622e-06 (0.00081%).
- gnomAD v4.1 best subpopulation AF 1.33697e-05 (0.00134%).
- PALB2 PM2 is used only at Supporting strength with threshold ≤1/300
- 000 (0.000333%).
Sources
BA1 The highest observed population frequency in gnomAD v4.1 was 0.00134%, which is well below the PALB2 BA1 threshold of >0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > .1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 best subpopulation AF 1.33697e-05 (0.00134%).
- PALB2 BA1 threshold >0.1%.
Sources
BS1 The highest observed population frequency in gnomAD v4.1 was 0.00134% (1/74,796 alleles in African/African American individuals), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > .01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 best subpopulation AF 1.33697e-05 (0.00134%).
- PALB2 BS1 threshold >0.01%.
Sources
BP4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, below the PALB2 BP4 splicing threshold of ≤0.1. However, BP4 is not appropriate here because the variant itself causes a frameshift and predicted truncation, so the available computational evidence does not support no impact on the gene product. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing (SpliceAI ≤ 0.1)
Evidence considered
- SpliceAI max delta score 0.00.
- Variant is a frameshift with predicted truncation.
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no exact-variant case-control study, odds ratio, relative risk, or p-value meeting the PALB2 PS4 threshold was identified. Published data support increased breast cancer risk for truncating PALB2 variants as a group, but that does not establish PS4 for this specific variant. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤ 0.05 AND (OR, HR, or RR ≥ 3 or lower 95% CI ≥ 1.5)
Evidence considered
- ClinVar contains multiple pathogenic/likely pathogenic submissions for this variant.
- Published PALB2 truncating-variant case-control data are gene-level rather than exact-variant specific.
Still missing
- No exact-variant enrichment study was identified.
- No case-control statistic meeting the PALB2 PS4 threshold was available for this variant.
Sources
PM3 No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia or another recessive PALB2-related presentation, so PM3 could not be applied. Details ▾Hide ▴
Rule
PM3_Supporting = 1 point; PM3 = 2 points; PM3_Strong ≥ 4 points; PM3_VeryStrong ≥ 8 points
Evidence considered
- PALB2 PM3 requires point-based recessive evidence.
- Reviewed gene-level recessive disease context for PALB2.
Still missing
- No phase-confirmed biallelic observations were identified.
- No PM3 point-based Fanconi anemia evidence was available.
Sources
PP1 No segregation data were identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 / 0.60 / 1.26 or Bayes Factor ≥2:1 / 4:1 / 18:1 for Supporting / Moderate / Strong
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence or affected-relative counts in the recessive setting.
Still missing
- No family-based cosegregation data were identified.
- No Bayes factor or LOD score was available.
Sources
BS2 No evidence was identified showing this variant in the healthy adult context or recessive point-based framework required for BS2, so the criterion could not be assessed. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2_Strong ≥ 4 points
Evidence considered
- PALB2 BS2 requires point-based evidence and excludes population datasets such as gnomAD.
Still missing
- No BS2 point-based observations were identified.
- No informative unaffected adult or recessive-context evidence was available.
Sources
BS4 No quantitative non-segregation data were identified for this variant. The PALB2 specification requires a Bayes factor or LOD-based segregation assessment, and no family data meeting those thresholds were available. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤0.053:1; Moderate and Supporting downgrades per PALB2 specification
Evidence considered
- PALB2 BS4 requires quantitative segregation evidence
- none was available for this variant.
Still missing
- Family-level segregation or non-segregation data were not identified.
- No Bayes factor or LOD score was available.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 in PALB2 is restricted to the splicing table context and is not applicable to this frameshift deletion. Details ▾Hide ▴
Evidence considered
- PALB2 PS1 is directed to splicing-table use and not to truncating frameshift variants.
Sources
PS2 N/APS2 is not used by this PALB2 expert specification. Details ▾Hide ▴
PS3 N/APS3 is not used by this PALB2 expert specification for this evidence type. Details ▾Hide ▴
PM1 N/APM1 is not used for PALB2 because pathogenic missense variation has not been established as a disease mechanism for this gene. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP marks PM1 as not applicable.
- Cancer Hotspots review did not identify a statistically significant hotspot at this residue.
Sources
PM4 N/AThis variant is a frameshift deletion, and the PALB2 specification states that PM4 is not used for this variant type. Details ▾Hide ▴
Evidence considered
- PALB2 PM4 is reserved for stop-loss variants and is not used for frameshift variants.
Sources
PM6 N/APM6 is not used by this PALB2 expert specification. Details ▾Hide ▴
PP2 N/APP2 is not used for PALB2 because missense variation is not an established disease mechanism for this gene, and this variant is not missense. Details ▾Hide ▴
PP3 N/APP3 in the PALB2 specification is used for predicted splice impact in selected silent, missense, in-frame, or noncanonical intronic variants. This frameshift variant has a SpliceAI maximum delta score of 0.00 and does not fit the PP3 use case. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- PALB2 PP3 rule is limited to specified splicing contexts and is not intended to be stacked with PVS1-based truncating evidence.
Sources
PP4 N/APP4 is not used for autosomal dominant PALB2-related cancer predisposition in this specification. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP marks PP4 as not applicable for the autosomal dominant condition.
Sources
BS3 N/ABS3 is not used by this PALB2 expert specification for this type of evidence assessment. Details ▾Hide ▴
BP1 N/ABP1 is intended for missense variants, whereas this variant is a frameshift deletion. Details ▾Hide ▴
BP2 N/ABP2 is not used by this PALB2 expert specification. Details ▾Hide ▴
BP3 N/ABP3 is not used for PALB2 under this specification. Details ▾Hide ▴
BP5 N/ABP5 is not used by the PALB2 specification because co-occurrence with other pathogenic variants is not considered informative enough for this gene. Details ▾Hide ▴
BP6 N/ABP6 is not used by this PALB2 expert specification. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or deep intronic variants, whereas this variant is an exonic frameshift deletion. Details ▾Hide ▴
Evidence considered
- PALB2 BP7 is for synonymous or deep intronic contexts
- or RNA evidence of normal splicing in those contexts.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.3362del
- Protein (HGVS p.)
- NP_078951.2:p.(Gly1121ValfsTer3)
- GRCh38
- chr16:23603657 AC>A
- GRCh37
- chr16:23614978 AC>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
13 / 1,613,660 alleles
AF 8.06e-06 · 0 homozygotes · FAF 5.42e-06
gnomAD v2.1
1 / 251,320 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 8.1e-06 · 13 / 1,613,660 alleles · 0 hom · FAF 5.4e-06
| African/African American1 / 74,796 | 1.3e-05 |
| European (non-Finnish)12 / 1,179,962 | 1e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4e-06 · 1 / 251,320 alleles · 0 hom
| European (non-Finnish)1 / 113,654 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, 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= 8.05622e-06; MAF= 0.00081%, 13/1613660 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33697e-05; MAF= 0.00134%, 1/74796 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79863e-06; MAF= 0.00088%, 1/113654 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, below the PALB2 BP4 splicing threshold of ≤0.1. However, BP4 is not appropriate here because the variant itself causes a frameshift and predicted truncation, so the available computational evidence does not support no impact on the gene product. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing (SpliceAI ≤ 0.1)
Evidence considered
- SpliceAI max delta score 0.00.
- Variant is a frameshift with predicted truncation.
Sources
PP3 N/APP3 in the PALB2 specification is used for predicted splice impact in selected silent, missense, in-frame, or noncanonical intronic variants. This frameshift variant has a SpliceAI maximum delta score of 0.00 and does not fit the PP3 use case. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- PALB2 PP3 rule is limited to specified splicing contexts and is not intended to be stacked with PVS1-based truncating evidence.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, whereas this variant is an exonic frameshift deletion. Details ▾Hide ▴
Evidence considered
- PALB2 BP7 is for synonymous or deep intronic contexts
- or RNA evidence of normal splicing in those contexts.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
13 / 1,613,660 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/126739/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23614978-AC-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23603657-AC-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.3362…
- OncoKB ↗www.oncokb.org/gene/PALB2/G1121Vfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.3362del
- 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= 8.05622e-06; MAF= 0.00081%, 13/1613660 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33697e-05; MAF= 0.00134%, 1/74796 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79863e-06; MAF= 0.00088%, 1/113654 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Likely Pathogenic 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).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.