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PALB2c.2863dupPathogenic
Print report
Variant interpretation report

PALB2 c.2863dup, p.(Ser955LysfsTer2)

NM_024675.4:c.2863dup NP_078951.2:p.(Ser955LysfsTer2) View identifiers
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.

About PALB2

No gene-level summary was recorded for this case.

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
PVS1Very strong
PVS1 · very strong

This variant is a frameshift duplication predicted to create an early premature termination codon, p.(Ser955LysfsTer2), in PALB2. The PALB2 expert panel uses a gene-specific PVS1 framework, and loss of function is an established disease mechanism for PALB2-related cancer predisposition, supporting PVS1 at very strong strength for this truncating event.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v4.1, absent from gnomAD v2.1, and absent from gnomAD-Canada. The observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300,000) in gnomAD v4.

PM5Supporting
PM5 · supporting

The PALB2 expert panel repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift variant, p.(Ser955LysfsTer2), is upstream of p.Tyr1183 and therefore meets PM5 at supporting strength under the PALB2-specific rule.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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, PM2 supporting, PM5 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.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The PALB2 c.2863dup (p.(Ser955LysfsTer2)) variant has not been observed in somatic cancers in COSMIC and is absent from ClinVar.

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, placing the observed population frequency at 0%, below the PALB2 PM2_Supporting threshold of 0.000333% in gnomAD v4.

Published PALB2 studies and the expert-panel specification support loss of function as an established disease mechanism for PALB2-related cancer predisposition, and this duplication is predicted to cause an early truncating frameshift, p.(Ser955LysfsTer2).

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, supporting interpretation of the primary effect as a truncating frameshift rather than an alternative splice-driven event.

Met · 3

PVS1 Very strongThis variant is a frameshift duplication predicted to create an early premature termination codon, p.(Ser955LysfsTer2), in PALB2. The PALB2 expert panel uses a gene-specific PVS1 framework, and loss of function is an established disease mechanism for PALB2-related cancer predisposition, supporting PVS1 at very strong strength for this truncating event. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
  • Frameshift duplication NM_024675.4:c.2863dup with predicted protein consequence p.(Ser955LysfsTer2).
  • PALB2 loss of function is an established disease mechanism in the expert-panel framework.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingThis variant is absent from gnomAD v4.1, absent from gnomAD v2.1, and absent from gnomAD-Canada. The observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300,000) in gnomAD v4. 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.
  • Absent from gnomAD-Canada v1.0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
PM5 SupportingThe PALB2 expert panel repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift variant, p.(Ser955LysfsTer2), is upstream of p.Tyr1183 and therefore meets PM5 at supporting strength under the PALB2-specific rule. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183
Evidence considered
  • PALB2 uses a truncation-cutoff PM5 framework rather than classic same-residue missense PM5.
  • Predicted truncation p.(Ser955LysfsTer2) occurs upstream of p.Tyr1183.
Sources
cspec ↗pm5_candidates

Not met · 4 · evaluated, threshold not reached

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2. REVEL and BayesDel were not available for this indel, and the available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥ 0.2)
Evidence considered
  • SpliceAI max delta score 0.01.
  • REVEL/BayesDel not available for this duplication.
Sources
cspec ↗spliceai ↗
BA1 This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the BA1 threshold of 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > .1% in gnomAD v4 dataset
Evidence considered
  • Absent from gnomAD v4.1.
Sources
cspec ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the BS1 threshold of 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > .01% in gnomAD v4 dataset
Evidence considered
  • Absent from gnomAD v4.1.
Sources
cspec ↗gnomad_v4 ↗
BP4 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1. However, this benign splice prediction does not offset the independently damaging truncating frameshift effect, so BP4 is not applied. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤ 0.1). Do not apply for missense variants.
Evidence considered
  • SpliceAI max delta score 0.01.
Sources
cspec ↗spliceai ↗

Not assessed · 5 · no assessment recorded

PS4 No variant-specific case-control data were identified showing a statistically increased prevalence of this variant in affected individuals compared with controls, so PS4 cannot currently be assessed. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤ .05 and OR/HR/RR ≥ 3 or lower 95% CI ≥ 1.5
Evidence considered
  • No qualifying variant-specific case-control evidence identified.
Still missing
  • No variant-specific case-control statistics were identified.
Sources
PMID:28779002 ↗
PM3 No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot currently be assessed. Details ▾Hide ▴
Rule
Use Fanconi anemia PM3 point-based framework
Evidence considered
  • No qualifying recessive trans observations identified.
Still missing
  • No phase-confirmed trans observations in Fanconi anemia identified.
PP1 No segregation data were identified that would allow calculation of a PALB2-specific LOD score or Bayes factor, so PP1 cannot currently be assessed. Details ▾Hide ▴
Rule
AD: LOD ≥ 0.3 / 0.6 / 1.26 or LR ≥ 2:1 / 4:1 / 18:1; AR: segregation in affected relatives
Evidence considered
  • No segregation evidence identified.
Still missing
  • No family segregation data identified.
BS2 No well-documented observations of this variant in unaffected individuals meeting the PALB2/Fanconi anemia BS2 framework were identified, so BS2 cannot currently be assessed. Details ▾Hide ▴
Rule
Use Fanconi anemia BS2 point-based framework
Evidence considered
  • No BS2-qualifying observations identified.
Still missing
  • No qualifying unaffected adult observations identified.
BS4 No non-segregation data were identified that would allow calculation of a PALB2-specific LOD score or Bayes factor, so BS4 cannot currently be assessed. Details ▾Hide ▴
Rule
LOD ≤ -0.32 / -0.64 / -1.28 or LR ≤ 0.48 / 0.23 / 0.053:1
Evidence considered
  • No non-segregation evidence identified.
Still missing
  • No family non-segregation data identified.
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a truncating frameshift variant, and the PALB2 PS1 specification is restricted to splice-based comparisons rather than truncating variants. PS1 is therefore not applicable. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
  • PALB2 PS1 is reserved for splice-table use.
Sources
cspec ↗
PS2 VCEPThe PALB2 expert panel does not use PS2 for this disorder framework. PS2 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PS2 marked not applicable in the expert-panel specification.
Sources
cspec ↗
PS3 VCEPThe PALB2 expert panel does not apply PS3 for protein functional assays in this framework. PS3 is therefore not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PS3 marked not applicable in the expert-panel specification.
Sources
cspec ↗PMID:18053174 ↗PMID:25529982 ↗PMID:28279176 ↗PMID:28779002 ↗PMID:28858227 ↗PMID:29484706 ↗
PM1 VCEPThe PALB2 expert panel does not use PM1 because missense pathogenic variation is not yet an established PALB2 disease mechanism. PM1 is not applicable to this truncating variant. Details ▾Hide ▴
Evidence considered
  • PALB2 PM1 marked not applicable in the expert-panel specification.
Sources
cspec ↗PMID:18053174 ↗PMID:25529982 ↗PMID:28279176 ↗PMID:28779002 ↗PMID:28858227 ↗PMID:29484706 ↗
PM4 VCEPThe PALB2 expert panel does not use PM4 for frameshift variants and limits PM4 to stop-loss variants. PM4 is therefore not applicable. Details ▾Hide ▴
VCEP rule
Do not use for in-frame insertions/deletions less than a single exon; use for stop-loss variants only
Evidence considered
  • PALB2 PM4 is restricted to stop-loss variants.
Sources
cspec ↗
PM6 VCEPThe PALB2 expert panel does not use PM6 for this disorder framework. PM6 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PM6 marked not applicable in the expert-panel specification.
Sources
cspec ↗
PP2 VCEPThe PALB2 expert panel does not use PP2 because missense variation is not an established disease mechanism. PP2 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PP2 marked not applicable in the expert-panel specification.
Sources
cspec ↗
PP4 VCEPThe PALB2 expert panel does not use PP4 for the autosomal dominant cancer-predisposition setting because the phenotype is genetically heterogeneous. PP4 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PP4 is not used for AD disease in this framework.
Sources
cspec ↗
PP5 VCEPThis criterion is not used by the PALB2 expert panel. PP5 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 PP5 marked not applicable in the expert-panel specification.
Sources
cspec ↗
BS3 VCEPThe PALB2 expert panel does not apply BS3 for protein functional assays in this framework. BS3 is therefore not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 BS3 marked not applicable in the expert-panel specification.
Sources
cspec ↗PMID:18053174 ↗PMID:25529982 ↗PMID:28279176 ↗PMID:28779002 ↗PMID:28858227 ↗PMID:29484706 ↗
BP1 N/AThis criterion applies to missense variants. Because this variant is a frameshift duplication rather than a missense change, BP1 is not applicable. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
  • Variant is a frameshift duplication
  • not a missense variant.
Sources
cspec ↗
BP2 VCEPThe PALB2 expert panel does not use BP2 in this framework. BP2 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 BP2 marked not applicable in the expert-panel specification.
Sources
cspec ↗
BP3 VCEPThis criterion is not used by the PALB2 expert panel for this variant type. BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 BP3 marked not applicable in the expert-panel specification.
Sources
cspec ↗
BP5 VCEPThe PALB2 expert panel does not use BP5 in this framework. BP5 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 BP5 marked not applicable in the expert-panel specification.
Sources
cspec ↗
BP6 VCEPThis criterion is not used by the PALB2 expert panel. BP6 is not applicable. Details ▾Hide ▴
Evidence considered
  • PALB2 BP6 marked not applicable in the expert-panel specification.
Sources
cspec ↗
BP7 N/AThis criterion is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those variant classes. Because this variant is a coding frameshift duplication, BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based lack of aberrant splice defect in those classes
Evidence considered
  • Variant is a coding frameshift duplication.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.2863dup
Protein (HGVS p.)
NP_078951.2:p.(Ser955LysfsTer2)
GRCh38
chr16:23623101 C>CT
GRCh37
chr16:23634422 C>CT

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +29 bp
0.000
SpliceAI acceptor gainat -1 bp
0.010
SpliceAI donor lossat -132 bp
0.000
SpliceAI donor gainat +0 bp
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2. REVEL and BayesDel were not available for this indel, and the available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥ 0.2)
Evidence considered
  • SpliceAI max delta score 0.01.
  • REVEL/BayesDel not available for this duplication.
Sources
cspec ↗spliceai ↗
BP4 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1. However, this benign splice prediction does not offset the independently damaging truncating frameshift effect, so BP4 is not applied. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤ 0.1). Do not apply for missense variants.
Evidence considered
  • SpliceAI max delta score 0.01.
Sources
cspec ↗spliceai ↗
BP7 N/AThis criterion is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those variant classes. Because this variant is a coding frameshift duplication, BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based lack of aberrant splice defect in those classes
Evidence considered
  • Variant is a coding frameshift duplication.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
    No paper-specific finding is recorded.
    PMID 18053174 ↗
  • A novel PALB2 truncating mutation in an Italian family with male breast cancer.
    No paper-specific finding is recorded.
    PMID 25529982 ↗
  • PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
    No paper-specific finding is recorded.
    PMID 28279176 ↗
  • Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
    No paper-specific finding is recorded.
    PMID 28779002 ↗
  • The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
    No paper-specific finding is recorded.
    PMID 28858227 ↗
  • Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes.
    No paper-specific finding is recorded.
    PMID 29484706 ↗

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 Recorded maximum delta 0.010 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

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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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.