About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.886dup, p.(Met296AsnfsTer7)
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: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This frameshift duplication in exon 4 introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), far upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), and is predicted to trigger nonsense-mediated decay. PALB2 loss of function is an established disease mechanism under the ClinGen PALB2 VCEP (v1.2.0).
PM2Supporting
PM2 · supporting
This variant has an overall allele frequency of 0.00031% (5/1,613,880 alleles) in gnomAD v4.1, which is below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (1/300,000). No homozygotes have been observed.
PM5Supporting
PM5 · supporting
This frameshift variant introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), satisfying the PALB2 VCEP PM5_Supporting rule for truncating variants.
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.
gnomAD v4.1
gnomAD v2.1
Population frequency
5 / 1,613,880 alleles
gnomAD v4.1: 5 / 1,613,880 alleles. Recorded AF 3.09812e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
8 reported laboratory submissions
8 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55163417, n = 3 times).
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 · 6 not met · 0 not assessed · 19 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_024675.4:c.886dupA (p.Met296AsnfsTer7) is a frameshift duplication in exon 4 of PALB2 that introduces a premature termination codon predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen PALB2 VCEP v1.2.0.
The variant is present in gnomAD v4.1 at an overall frequency of 0.00031% (5/1,613,880 alleles, no homozygotes), below the PALB2 VCEP PM2_Supporting threshold of 0.000333%, satisfying PM2 at supporting strength.
The premature termination codon at residue 302 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, satisfying PM5_Supporting under the PALB2 VCEP.
Under the ACMG/AMP 2015 combining rules adopted by the PALB2 VCEP, one Very Strong (PVS1) plus two Supporting (PM2, PM5) criteria satisfies Rule 4, yielding a classification of Pathogenic.
No criteria match.
Met · 3
PVS1 Very strongThis frameshift duplication in exon 4 introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), far upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), and is predicted to trigger nonsense-mediated decay. PALB2 loss of function is an established disease mechanism under the ClinGen PALB2 VCEP (v1.2.0). Details ▾Hide ▴
Evidence considered
- Frameshift variant predicted to cause NMD (stop at codon 302 in exon 4 of 13)
- Truncation upstream of p.Tyr1183
- the most C-terminal known pathogenic variant in PALB2
- PALB2 loss-of-function is an established germline disease mechanism per ClinGen PALB2 VCEP v1.2.0
Sources
PM2 SupportingThis variant has an overall allele frequency of 0.00031% (5/1,613,880 alleles) in gnomAD v4.1, which is below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (1/300,000). No homozygotes have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall frequency: 0.00031% (5/1
- 613
- 880)
- below PM2_Supporting threshold of 0.000333%
- No homozygotes observed
- Absent from gnomAD v2.1 and gnomAD-Canada v1.0
Sources
PM5 SupportingThis frameshift variant introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), satisfying the PALB2 VCEP PM5_Supporting rule for truncating variants. Details ▾Hide ▴
Evidence considered
- Premature termination codon at residue 302
- upstream of p.Tyr1183 cutoff
- Consistent with PALB2 VCEP PM5_Supporting rule for frameshifting variants
Sources
pm5_candidatescspec ↗
Not met · 6 · evaluated, threshold not reached
PS4 No case-control study has been identified that evaluates NM_024675.4:c.886dupA specifically with an odds ratio ≥3 or lower 95% CI ≥1.5 and p≤0.05, as required by the PALB2 VCEP PS4 rule. Details ▾Hide ▴
Evidence considered
- No variant-specific case-control data available in the literature or ClinVar submissions
Still missing
- Variant-specific case-control data not available
Sources
PP1 No co-segregation data (LOD scores, Bayes factors, or affected relative counts) are available for NM_024675.4:c.886dupA. Details ▾Hide ▴
Evidence considered
- No segregation data identified in the reviewed literature or ClinVar submissions
Still missing
- Co-segregation data not available
Sources
BA1 The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, well below the BA1 threshold of >0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF: 0.00175%
- below BA1 threshold of >0.1%
Sources
BS1 The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, below the BS1 threshold of >0.01%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF: 0.00175%
- below BS1 threshold of >0.01%
Sources
BS2 No individuals homozygous or compound heterozygous for this variant have been reported with a Fanconi anemia phenotype, and no BS2 proband-level data are available for point assignment under the PALB2 VCEP Fanconi Anemia BS2 tables. Details ▾Hide ▴
Evidence considered
- No homozygotes observed in gnomAD
- No Fanconi anemia proband data available
Still missing
- No proband-level data for Fanconi anemia BS2 point assignment
Sources
BS4 No segregation data demonstrating lack of co-segregation (LOD ≤ -0.32 or Bayes Factor ≤0.48) with disease is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Segregation data not available
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 under the PALB2 VCEP (v1.2.0) is applicable only to splicing variants with reference to the PALB2 PS1 Splicing table; this is a frameshift duplication. Details ▾Hide ▴
Sources
PS2 VCEPPS2 is designated Not Applicable by the PALB2 VCEP (v1.2.0): informative de novo occurrences have not been observed for autosomal dominant PALB2-related disease. Details ▾Hide ▴
Sources
PS3 VCEPPS3 is designated Not Applicable by the PALB2 VCEP (v1.2.0); functional studies for protein-level effects are not part of the current PALB2 variant interpretation framework. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is designated Not Applicable by the PALB2 VCEP (v1.2.0): missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease. Details ▾Hide ▴
Sources
PM4 VCEPPM4 under the PALB2 VCEP (v1.2.0) is restricted to stop-loss variants only; this is a frameshift duplication. Details ▾Hide ▴
Sources
PM6 VCEPPM6 is designated Not Applicable by the PALB2 VCEP (v1.2.0): informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is designated Not Applicable by the PALB2 VCEP (v1.2.0): missense is not yet confirmed or refuted as a mechanism of disease for PALB2. Details ▾Hide ▴
Sources
PP3 N/APP3 under the PALB2 VCEP (v1.2.0) is applicable only to splicing variants with SpliceAI ≥0.2. This frameshift variant has a SpliceAI max delta score of 0.01, and PP3 is excluded for missense variants; it does not apply to frameshift variants. Details ▾Hide ▴
PP4 VCEPPP4 is designated Not Applicable by the PALB2 VCEP (v1.2.0): breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BS3 VCEPBS3 is designated Not Applicable by the PALB2 VCEP (v1.2.0). Details ▾Hide ▴
Sources
BP1 N/ABP1 under the PALB2 VCEP (v1.2.0) applies to all missense variants only; this is a frameshift duplication. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is designated Not Applicable by the PALB2 VCEP (v1.2.0). Details ▾Hide ▴
Sources
BP3 VCEPBP3 is designated Not Applicable by the PALB2 VCEP (v1.2.0): small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity, and PALB2 does not have repetitive regions without known function. Details ▾Hide ▴
Sources
BP4 N/AUnder the PALB2 VCEP (v1.2.0), BP4 for splice predictions cannot be applied in addition to PVS1, which has been assigned for this frameshift variant. Additionally, BP4 is applicable only to splicing variants with SpliceAI ≤0.1. Details ▾Hide ▴
Evidence considered
- PVS1 is applied
- BP4 splice prediction stacking is prohibited by VCEP
- SpliceAI max delta: 0.01
Sources
BP5 VCEPBP5 is designated Not Applicable by the PALB2 VCEP (v1.2.0): cases with multiple pathogenic variants have been observed with no noticeable phenotype difference, and PALB2 has moderate penetrance. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is designated Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP7 N/ABP7 under the PALB2 VCEP (v1.2.0) applies to synonymous and deep intronic variants only; this is a frameshift duplication. Details ▾Hide ▴
Sources
PS5 N/APS5 is not defined in the PALB2 VCEP framework (v1.2.0); the ClinGen SVI VCEP Review Committee designates the closely related PP5 as Not Applicable for this VCEP. Details ▾Hide ▴
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.886dup
- Protein (HGVS p.)
- NP_078951.2:p.(Met296AsnfsTer7)
- GRCh38
- chr16:23635659 A>AT
- GRCh37
- chr16:23646980 A>AT
- ClinVar
- 410157
- COSMIC
- COSV55163417
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
5 / 1,613,880 alleles
AF 3.1e-06 · 0 homozygotes · FAF 1.75e-05
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,613,880 alleles · 0 hom · FAF 1.7e-05
| African/African American4 / 74,870 | 5.3e-05 |
| East Asian1 / 44,882 | 2.2e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.09812e-06; MAF= 0.00031%, 5/1613880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.34259e-05; MAF= 0.00534%, 4/74870 alleles, homozygotes = 0); grpmax FAF= 1.747e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 under the PALB2 VCEP (v1.2.0) is applicable only to splicing variants with SpliceAI ≥0.2. This frameshift variant has a SpliceAI max delta score of 0.01, and PP3 is excluded for missense variants; it does not apply to frameshift variants. Details ▾Hide ▴
BP4 N/AUnder the PALB2 VCEP (v1.2.0), BP4 for splice predictions cannot be applied in addition to PVS1, which has been assigned for this frameshift variant. Additionally, BP4 is applicable only to splicing variants with SpliceAI ≤0.1. Details ▾Hide ▴
Evidence considered
- PVS1 is applied
- BP4 splice prediction stacking is prohibited by VCEP
- SpliceAI max delta: 0.01
Sources
BP7 N/ABP7 under the PALB2 VCEP (v1.2.0) applies to synonymous and deep intronic variants only; this is a frameshift duplication. Details ▾Hide ▴
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 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
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PMID 18053174 ↗Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.Screened PALB2 coding exons in 50 French-Canadian women with early-onset breast cancer. Reports the c.2323C→T (p.Glu775X) founder mutation and other novel truncating mutations. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 25529982 ↗A novel PALB2 truncating mutation in an Italian family with male breast cancer.Reports a novel PALB2 truncating mutation c.1285_1286delAinsTC (p.I429SfsX12) in an Italian family with male breast cancer. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 28279176 ↗PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.Screened PALB2 exons in 460 BRCA1/2-negative breast and ovarian cancer patients from Poland. Reports recurrent PALB2 mutations in the Polish population. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 28779002 ↗Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.Sequenced ATM, CHEK2, PALB2, and XRCC2 coding regions in 13,087 breast cancer cases and 5,488 controls from East Anglia, UK. Evaluates association of rare protein-truncating variants with breast cancer risk at gene level. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 28858227 ↗The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.Comprehensive review of PALB2 biology, its role in DNA damage response, and cancer predisposition. Discusses PALB2 domains, interaction partners, and general mutation spectrum. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 17200671 ↗Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.Reid S et al. · 2007Reports biallelic PALB2 mutations in seven families with Fanconi anemia subtype FA-N. Identifies pathogenic PALB2 mutations in the FA context. NM_024675.4:c.886dupA was not identified among the reported mutations.Does not name this variant
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PMID 25099575 ↗Breast-cancer risk in families with mutations in PALB2.Antoniou AC et al. · 2014Reports breast cancer risk estimates for PALB2 loss-of-function mutation carriers in 154 families. Discusses PALB2 truncating, splice, and deletion mutations at gene level. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the classification framework and evidence combination rules. Does not discuss specific PALB2 variants. NM_024675.4:c.886dupA was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes Sherloc, a refinement of ACMG-AMP variant classification criteria. Provides classification framework methodology. Does not discuss specific PALB2 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
5 / 1,613,880 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
8 Pathogenic
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/410157/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646980-A-AT?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635659-A-AT?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-23635659-A-AT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.886d…
- OncoKB ↗www.oncokb.org/gene/PALB2/M296Nfs*7
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120588690
- 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= 3.09812e-06; MAF= 0.00031%, 5/1613880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.34259e-05; MAF= 0.00534%, 4/74870 alleles, homozygotes = 0); grpmax FAF= 1.747e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories). (ClinVarID = 410157)
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 previously been reported in somatic cancers (COSMIC; COSV55163417, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.