About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1042C>A, p.(Gln348Lys)
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 variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic missense variants are thought to be exceedingly rare in this gene. BP1 is met at supporting strength.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched 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
49 / 1,613,732 alleles
gnomAD v4.1: 49 / 1,613,732 alleles. Recorded AF 3.03644e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89383e-05; MAF= 0.00389%, 11/282498 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.52832e-05; MAF= 0.00853%, 11/128982 alleles, homozygotes = 0); grpmax FAF= 4.742e-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
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 · 7 not met · 4 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.1042C>A (p.Gln348Lys; Q348K) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions.
This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00304% (49/1,613,732 alleles) with a highest observed population frequency of 0.00415% in European non-Finnish individuals; this is below the PALB2 BS1 threshold of 0.01% and above the PM2 threshold of 0.000333%.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2.
Because this is a PALB2 missense variant, BP1 is met at supporting strength under the PALB2 specification, while PVS1 is not met because the variant is not a truncating or canonical splice-site loss-of-function change.
No criteria match.
Met · 1
BP1 SupportingThis variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic missense variants are thought to be exceedingly rare in this gene. BP1 is met at supporting strength. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant is missense p.(Gln348Lys)
- PALB2 CSPEC: apply BP1 to all missense variants
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1. The generic PVS1 scaffold states that c.1042C>A is not a nonsense, frameshift, or canonical ±1,2 splice variant, so PVS1 is not met. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 CSPEC includes PVS1 guidance
- pvs1_gene_context: loss of function is an established PALB2 disease mechanism
- pvs1_variant_assessment: variant bucket other
- apply_generic_pvs1_framework=false
Sources
PS1 No evidence was identified that this variant has the same established pathogenic protein or splicing consequence as a previously classified pathogenic PALB2 variant, so PS1 is not met. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- PALB2 missense change p.(Gln348Lys)
- SpliceAI max delta score 0.00
Still missing
- No PALB2 PS1 splicing-table match was identified.
Sources
PS4 This variant has been reported in ClinVar, but no qualifying case-control evidence was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥3, or a lower 95% confidence interval ≥1.5. PS4 is therefore not met. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- ClinVar shows mixed submissions including uncertain significance
- likely benign
- and benign
- No case-control metric meeting PALB2 PS4 threshold was identified
Still missing
- No qualifying PALB2 variant-specific case-control study was identified.
Sources
PM2 Population frequency does not meet the PALB2 PM2_Supporting threshold. In gnomAD v4.1, the variant has a grpmax filtering allele frequency of 0.003179%, which is above the PM2 threshold of 0.000333% (1/300,000), so PM2 is not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 grpmax FAF 3.179e-05 (0.003179%)
- PM2_Supporting threshold ≤1/300
- 000 (0.000333%)
Sources
PP3 SpliceAI predicts no splice effect for this variant, with a maximum delta score of 0.00. This is below the PALB2 PP3 splicing threshold of ≥0.2, so PP3 is not met. Details ▾Hide ▴
Rule
Splicing PP3 applies for predicted impact via SpliceAI ≥0.2
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.0
- max delta score 0.00
Sources
BA1 Population frequency is far below the PALB2 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.003179%, which is below the 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 3.179e-05 (0.003179%)
- BA1 threshold >0.1%
Sources
BS1 Population frequency does not reach the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00415% in European non-Finnish individuals, which is below the 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 best subpopulation AF 4.15285e-05 (0.00415%) in NFE
- BS1 threshold >0.01%
Sources
Not assessed · 4 · no assessment recorded
PM3 No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in a proband informative for Fanconi anemia scoring, so PM3 could not be assessed. Details ▾Hide ▴
PP1 No segregation data were identified to calculate a qualifying LOD score or Bayes factor for PALB2-related disease, so PP1 could not be assessed. Details ▾Hide ▴
Rule
AD condition: LOD ≥0.3 for supporting, ≥0.60 for moderate, ≥1.26 for strong; AR condition: segregation in affected relatives
Evidence considered
- No segregation evidence available in reviewed materials
Still missing
- No family segregation dataset or LOD/Bayes factor was identified.
Sources
BS2 No qualifying observations were identified in unaffected individuals that would permit point-based BS2 scoring under the PALB2 Fanconi anemia framework. Population database observations alone are not sufficient for this criterion, so BS2 could not be assessed. Details ▾Hide ▴
Rule
Use Fanconi Anemia BS2 tables for point-based scoring
Evidence considered
- PALB2 CSPEC states not to use population-based cohorts such as gnomAD for BS2
Still missing
- No qualifying unaffected individual data meeting PALB2 BS2 scoring requirements were identified.
Sources
BS4 No quantitative non-segregation data were identified to calculate a qualifying LOD score or Bayes factor, so BS4 could not be assessed. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor ≤0.053:1 for strong; lesser thresholds for moderate/supporting
Evidence considered
- No BS4 segregation evidence available in reviewed materials
Still missing
- No family non-segregation dataset or LOD/Bayes factor was identified.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis PALB2 specification does not use PS2 for this disease context, so PS2 is not applicable. Details ▾Hide ▴
PS3 N/AThis PALB2 specification does not use PS3 for this variant assessment framework, so PS3 is not applicable. Details ▾Hide ▴
PM1 N/AThe PALB2 specification does not use PM1, so PM1 is not applicable. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution, and the PALB2 specification does not apply PM4 to missense variants. PM4 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense p.(Gln348Lys)
- PALB2 CSPEC restricts PM4 to stop-loss use
Sources
PM5 N/AThe PALB2 PM5_Supporting rule is specified for truncating or qualifying splice variants upstream of p.Tyr1183, not for this missense variant, so PM5 is not applicable. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or qualifying splice variants
Evidence considered
- Variant is missense p.(Gln348Lys)
Sources
PM6 N/AThis PALB2 specification does not use PM6 in this disease context, so PM6 is not applicable. Details ▾Hide ▴
PP2 N/AThe PALB2 specification does not use PP2, so PP2 is not applicable. Details ▾Hide ▴
PP4 N/AThe PALB2 specification does not use PP4 for the autosomal dominant cancer predisposition context, so PP4 is not applicable. Details ▾Hide ▴
PP5 N/AThis PALB2 specification does not use PP5, so PP5 is not applicable. Details ▾Hide ▴
BS3 N/AThe PALB2 specification does not apply BS3 for protein functional evidence in this framework, so BS3 is not applicable. Details ▾Hide ▴
BP2 N/AThe PALB2 specification does not use BP2, so BP2 is not applicable. Details ▾Hide ▴
BP3 N/AThe PALB2 specification does not use BP3, so BP3 is not applicable. Details ▾Hide ▴
BP4 N/AAlthough SpliceAI predicts no splice impact for this variant with a maximum delta score of 0.00, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applicable. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI ≤0.1; do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.00
- PALB2 CSPEC: do not apply BP4 for missense variants
Sources
BP5 N/AThe PALB2 specification does not use BP5, so BP5 is not applicable. Details ▾Hide ▴
BP6 N/AThe PALB2 specification does not use BP6, so BP6 is not applicable. Details ▾Hide ▴
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA evidence
Evidence considered
- Variant is missense p.(Gln348Lys)
- PALB2 BP7 is specified for synonymous and deep intronic contexts or RNA evidence
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1042C>A
- Protein (HGVS p.)
- NP_078951.2:p.(Gln348Lys)
- GRCh38
- chr16:23635504 G>T
- GRCh37
- chr16:23646825 G>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
49 / 1,613,732 alleles
AF 3.04e-05 · 0 homozygotes · FAF 3.18e-05
gnomAD v2.1
11 / 282,498 alleles
AF 3.89e-05 · 0 homozygotes · FAF 4.74e-05
By genetic ancestry
gnomAD v4.1
AF 3e-05 · 49 / 1,613,732 alleles · 0 hom · FAF 3.2e-05
| European (non-Finnish)49 / 1,179,912 | 4.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,498 alleles · 0 hom · FAF 4.7e-05
| European (non-Finnish)11 / 128,982 | 8.5e-05 |
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= 3.03644e-05; MAF= 0.00304%, 49/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.15285e-05; MAF= 0.00415%, 49/1179912 alleles, homozygotes = 0); grpmax FAF= 3.179e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89383e-05; MAF= 0.00389%, 11/282498 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.52832e-05; MAF= 0.00853%, 11/128982 alleles, homozygotes = 0); grpmax FAF= 4.742e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no splice effect for this variant, with a maximum delta score of 0.00. This is below the PALB2 PP3 splicing threshold of ≥0.2, so PP3 is not met. Details ▾Hide ▴
Rule
Splicing PP3 applies for predicted impact via SpliceAI ≥0.2
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.0
- max delta score 0.00
Sources
BP4 N/AAlthough SpliceAI predicts no splice impact for this variant with a maximum delta score of 0.00, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applicable. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI ≤0.1; do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.00
- PALB2 CSPEC: do not apply BP4 for missense variants
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or qualifying RNA evidence
Evidence considered
- Variant is missense p.(Gln348Lys)
- PALB2 BP7 is specified for synonymous and deep intronic contexts or RNA evidence
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.02. BayesDel score = -0.53199.
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
49 / 1,613,732 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/141588/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646825-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635504-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1042…
- OncoKB ↗www.oncokb.org/gene/PALB2/Q348K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1042C%3EA
- 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= 3.03644e-05; MAF= 0.00304%, 49/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.15285e-05; MAF= 0.00415%, 49/1179912 alleles, homozygotes = 0); grpmax FAF= 3.179e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89383e-05; MAF= 0.00389%, 11/282498 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.52832e-05; MAF= 0.00853%, 11/128982 alleles, homozygotes = 0); grpmax FAF= 4.742e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.02. BayesDel score = -0.53199.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.