About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2329G>A, p.(Asp777Asn)
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants.
Recorded classification: Uncertain significance
Official PALB2 CSPEC/VCEP final-classification framework (cspec_ruleset; Richards et.al., 2015 combining rules in final_classification_framework.json) applied to 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
35 / 1,614,078 alleles
gnomAD v4.1: 35 / 1,614,078 alleles. Recorded AF 2.16842e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59089e-05; MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
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
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: 1 met · 3 not met · 5 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
The PALB2 c.2329G>A (p.Asp777Asn; p.D777N) variant has been observed in somatic cancers in COSMIC 3 times (COSV55162903) and has not been reported in ClinVar.
This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with highest observed frequency in East Asian individuals at 4/44,886 alleles (AF 0.00891%) and grpmax FAF 0.00298%, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL is low at 0.038; however, PALB2 missense specifications do not use PP3 or BP4 for missense variants.
No criteria match.
Met · 1
BP1 SupportingThis is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.4:c.2329G>A
- NP_078951.2:p.(Asp777Asn)
- PALB2 BP1 rule: apply to all missense variants
Sources
cspec ↗case_summary
Not met · 3 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 at 35/1,614,078 alleles (AF 0.00217%), with grpmax FAF 0.00298%. The observed frequency is 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.
Evidence considered
- gnomAD v4.1 total AC/AN 35/1614078; AF 2.1684206091651084e-05
- gnomAD v4.1 grpmax FAF 2.9770000000000005e-05
Sources
BA1 This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.9770000000000005e-05
Sources
BS1 This variant is present in gnomAD v4.1 with grpmax FAF 0.00298%, which is below the PALB2 BS1 threshold of 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.9770000000000005e-05
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been observed in COSMIC 3 times, but no germline case-control study showing significant enrichment in affected individuals was identified, so available evidence does not support PS4 assessment. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- COSMIC COSV55162903; somatic count 3
- ClinVar absent
- No PMIDs identified across evidence sources
Still missing
- No case-control study with p-value and effect-size data was identified.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia probands, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Apply PM3 using Fanconi anemia PM3 point tables.
Evidence considered
- No PMIDs identified across evidence sources
Still missing
- No phase-confirmed Fanconi anemia proband data were identified.
Sources
cspec ↗literature_pass
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD: LOD ≥0.3/0.6/1.26 or Bayes factor ≥2:1/4:1/18:1; AR: segregation in 1/2/≥3 affected relatives for Supporting/Moderate/Strong.
Evidence considered
- No PMIDs identified across evidence sources
Still missing
- No family segregation or Bayes factor/LOD data were identified.
Sources
cspec ↗literature_pass
BS2 No data were identified showing this variant in the number of unaffected individuals required by the PALB2 Fanconi anemia BS2 point system, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Apply BS2 using Fanconi anemia BS2 point tables.
Evidence considered
- No PMIDs identified across evidence sources
Still missing
- No qualifying unaffected-observation data were identified.
Sources
cspec ↗literature_pass
BS4 No nonsegregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
LOD ≤-0.32/-0.64/-1.28 or Bayes factor ≤0.48/0.23/0.053:1 for Supporting/Moderate/Strong.
Evidence considered
- No PMIDs identified across evidence sources
Still missing
- No family nonsegregation or Bayes factor/LOD data were identified.
Sources
cspec ↗literature_pass
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and PALB2 PVS1 is reserved for predicted loss-of-function variants using the PALB2 PVS1 decision tree. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- NM_024675.4:c.2329G>A; NP_078951.2:p.(Asp777Asn)
- PALB2 PVS1 rule: use PALB2 PVS1 decision tree
Sources
PS1 N/AAvailable evidence does not indicate that this missense variant matches a PALB2 splicing-table PS1 scenario, and the PALB2 PS1 specification is restricted to the PALB2 PS1 splicing table. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table.
Evidence considered
- PALB2 PS1 rule: use PALB2 PS1 Splicing table
- SpliceAI max delta score 0.01
Sources
PS2 N/APS2 is not used under the PALB2 specification. Details ▾Hide ▴
PS3 N/APS3 is not used under the PALB2 specification. Details ▾Hide ▴
PM1 N/APM1 is not used under the PALB2 specification. Details ▾Hide ▴
PM4 N/APM4 is not used under the PALB2 specification. Details ▾Hide ▴
PM5 N/AThis is a missense variant, whereas PALB2 PM5_Supporting is restricted to truncating or qualifying splice variants that create premature termination codons upstream of p.Tyr1183. Details ▾Hide ▴
Rule
Apply only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or qualifying NMD-prone splice variants.
Evidence considered
- NM_024675.4:c.2329G>A; NP_078951.2:p.(Asp777Asn)
- PALB2 PM5 rule is limited to truncating or qualifying splice variants upstream of p.Tyr1183
Sources
PM6 N/APM6 is not used under the PALB2 specification. Details ▾Hide ▴
PP2 N/APP2 is not used under the PALB2 specification. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice effect with a max delta score of 0.01, and PALB2 PP3 is not used for missense variants. Therefore PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: SpliceAI ≥0.2 for silent, missense/in-frame, and intronic variants outside ±1,2.
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 PP3 rule: missense do not use; splicing requires SpliceAI ≥0.2
Sources
PP4 N/APP4 is not used under the PALB2 specification. Details ▾Hide ▴
PP5 N/APP5 is not used under the PALB2 specification. Details ▾Hide ▴
BS3 N/ABS3 is not used under the PALB2 specification. Details ▾Hide ▴
BP2 N/ABP2 is not used under the PALB2 specification. Details ▾Hide ▴
BP3 N/ABP3 is not used under the PALB2 specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice effect with a max delta score of 0.01, but PALB2 BP4 is not used for missense variants. Therefore BP4 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 rule: missense do not use; splicing requires SpliceAI ≤0.1 and is not applied for missense variants
Sources
BP5 N/ABP5 is not used under the PALB2 specification. Details ▾Hide ▴
BP6 N/ABP6 is not used under the PALB2 specification. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence showing no aberrant splicing for silent/intronic variants.
Evidence considered
- NM_024675.4:c.2329G>A; NP_078951.2:p.(Asp777Asn)
- PALB2 BP7 applies to synonymous and qualifying deep intronic variants, or RNA evidence for silent/intronic variants
Sources
cspec ↗case_summary
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.2329G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Asp777Asn)
- GRCh38
- chr16:23629825 C>T
- GRCh37
- chr16:23641146 C>T
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
35 / 1,614,078 alleles
AF 2.17e-05 · 0 homozygotes · FAF 2.98e-05
gnomAD v2.1
4 / 251,432 alleles
AF 1.59e-05 · 0 homozygotes · FAF 1.9e-05
By genetic ancestry
gnomAD v4.1
AF 2.2e-05 · 35 / 1,614,078 alleles · 0 hom · FAF 3e-05
| East Asian4 / 44,886 | 8.9e-05 |
| Remaining individuals2 / 62,506 | 3.2e-05 |
| European (non-Finnish)28 / 1,180,018 | 2.4e-05 |
| South Asian1 / 91,068 | 1.1e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.6e-05 · 4 / 251,432 alleles · 0 hom · FAF 1.9e-05
| East Asian2 / 18,394 | 0.00011 |
| European (non-Finnish)2 / 113,736 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.16842e-05; MAF= 0.00217%, 35/1614078 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91146e-05; MAF= 0.00891%, 4/44886 alleles, homozygotes = 0); grpmax FAF= 2.977e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59089e-05; MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice effect with a max delta score of 0.01, and PALB2 PP3 is not used for missense variants. Therefore PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: SpliceAI ≥0.2 for silent, missense/in-frame, and intronic variants outside ±1,2.
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 PP3 rule: missense do not use; splicing requires SpliceAI ≥0.2
Sources
BP4 N/ASpliceAI predicts no significant splice effect with a max delta score of 0.01, but PALB2 BP4 is not used for missense variants. Therefore BP4 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 rule: missense do not use; splicing requires SpliceAI ≤0.1 and is not applied for missense variants
Sources
BP7 N/AThis is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence showing no aberrant splicing for silent/intronic variants.
Evidence considered
- NM_024675.4:c.2329G>A; NP_078951.2:p.(Asp777Asn)
- PALB2 BP7 applies to synonymous and qualifying deep intronic variants, or RNA evidence for silent/intronic variants
Sources
cspec ↗case_summary
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
35 / 1,614,078 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
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/?term=NM_024675.4%3Ac.2329G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641146-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23629825-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.2329…
- OncoKB ↗www.oncokb.org/gene/PALB2/D777N
- 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= 2.16842e-05; MAF= 0.00217%, 35/1614078 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91146e-05; MAF= 0.00891%, 4/44886 alleles, homozygotes = 0); grpmax FAF= 2.977e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59089e-05; MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55162903, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.