About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2831T>A, p.(Ile944Asn)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2 threshold of <=0.000333%. This supports rarity in the general population.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: BP1 supporting, PM2 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
3 / 1,577,962 alleles
gnomAD v4.1: 3 / 1,577,962 alleles. Recorded AF 1.90119e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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.
29 criteria with recorded statuses: 2 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.2831T>A (p.Ile944Asn) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel ClinGen submission.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2_Supporting threshold of 0.000333%.
No variant-specific reviewed functional evidence was identified in the retrieved materials, and the PALB2 expert specification does not apply PS3 or BS3 in this framework.
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification does not apply PP3 or BP4 to missense variants.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2 threshold of <=0.000333%. This supports rarity in the general population. Details ▾Hide ▴
Rule
PALB2 CSPEC PM2_Supporting: frequency <= 1/300,000 (0.000333%) in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v2.1
- gnomAD v4.1 AF 0.00019% (3/1577962)
- below PALB2 PM2 threshold 0.000333%.
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants. Details ▾Hide ▴
Rule
PALB2 CSPEC BP1: apply to all missense variants.
Evidence considered
- NM_024675.3:c.2831T>A predicts p.(Ile944Asn)
- a missense change
- PALB2 CSPEC applies BP1 to all missense variants.
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 Loss of function is an established PALB2 disease mechanism, but this variant is a missense substitution rather than a nonsense, frameshift, or canonical +/-1,2 splice variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
PALB2 CSPEC PVS1: use PALB2 PVS1 decision tree; generic scaffold does not support default PVS1 for this missense variant.
Evidence considered
- PALB2 LoF mechanism supported
- missense p.(Ile944Asn) is outside default null-variant buckets
- SpliceAI max delta 0.01.
Still missing
- No RNA study or other evidence showing a null effect was identified.
Sources
BA1 This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BA1 threshold of >0.1%. Details ▾Hide ▴
Rule
PALB2 CSPEC BA1: grpmax filtering AF >0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 total AF 0.00019% (3/1577962)
- highest observed population AF 0.00111%
- BA1 threshold >0.1%.
Sources
BS1 This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BS1 threshold of >0.01%. Details ▾Hide ▴
Rule
PALB2 CSPEC BS1: grpmax filtering AF >0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 total AF 0.00019% (3/1577962)
- highest observed population AF 0.00111%
- BS1 threshold >0.01%.
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, including an expert-panel submission, but no case-control study, odds ratio, or other quantified enrichment data specific to this variant were identified to support PS4. Details ▾Hide ▴
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 could not be assessed. Details ▾Hide ▴
Rule
PALB2 CSPEC PM3: apply using Fanconi anemia PM3 point tables.
Evidence considered
- PALB2 CSPEC PM3 uses a Fanconi anemia point-based framework.
Still missing
- No phase-confirmed Fanconi anemia proband data were identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Rule
PALB2 CSPEC PP1: apply using disease-specific segregation thresholds.
Evidence considered
- PALB2 CSPEC PP1 requires quantitative segregation evidence or affected-relative counts.
Still missing
- No pedigree
- meiosis count
- LOD score
- or Bayes factor was identified.
Sources
BS2 No data were identified showing the number of unaffected individuals or point-based evidence required to apply BS2 for PALB2-related Fanconi anemia. Details ▾Hide ▴
Rule
PALB2 CSPEC BS2: apply using Fanconi anemia BS2 point tables.
Evidence considered
- PALB2 CSPEC BS2 uses a point-based framework for unaffected individuals.
Still missing
- No unaffected-carrier or point-based BS2 data were identified.
Sources
BS4 No non-segregation data, LOD score, or Bayes factor were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Rule
PALB2 CSPEC BS4: LOD <= -1.28 / -0.64 / -0.32 or corresponding Bayes factor thresholds.
Evidence considered
- PALB2 CSPEC BS4 requires quantitative segregation evidence.
Still missing
- No family non-segregation dataset or quantitative segregation analysis was identified.
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThe PALB2 expert specification applies PS1 using a PALB2 splicing table. SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, and no evidence was identified showing the same pathogenic splicing consequence as a known pathogenic variant. Details ▾Hide ▴
Rule
PALB2 CSPEC PS1: use PALB2 PS1 splicing table.
Evidence considered
- PALB2 CSPEC PS1 uses a splicing table
- SpliceAI max delta 0.01 predicts no significant splice effect.
Still missing
- No PALB2 PS1 splicing-table match was identified for this variant.
Sources
PS2 N/AThe PALB2 expert specification does not use PS2 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PS2 not applicable.
Evidence considered
- PALB2 CSPEC lists PS2 as not applicable.
Sources
PS3 N/AThe PALB2 expert specification does not use PS3 for this gene, so pathogenic functional evidence was not applied in this framework. Details ▾Hide ▴
Rule
PALB2 CSPEC: PS3 not applicable.
Evidence considered
- PALB2 CSPEC lists PS3 as not applicable.
Sources
PM1 N/AThe PALB2 expert specification does not use PM1 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PM1 not applicable.
Evidence considered
- PALB2 CSPEC lists PM1 as not applicable.
Sources
PM4 N/AThis variant is a missense substitution, and the PALB2 expert specification does not apply PM4 to this variant type. Details ▾Hide ▴
Rule
PALB2 CSPEC PM4: not applicable for in-frame changes; use only for stop-loss variants.
Evidence considered
- PALB2 CSPEC lists PM4 as not applicable except for stop-loss variants.
Sources
PM5 N/AThis variant is a missense substitution. The PALB2 expert specification limits PM5 to qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183, so PM5 is not applicable. Details ▾Hide ▴
Rule
PALB2 CSPEC PM5_Supporting: apply to qualifying truncating/splice variants upstream of p.Tyr1183.
Evidence considered
- PALB2 CSPEC PM5_Supporting is limited to truncating or qualifying splice variants upstream of p.Tyr1183.
Sources
PM6 N/AThe PALB2 expert specification does not use PM6 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PM6 not applicable.
Evidence considered
- PALB2 CSPEC lists PM6 as not applicable.
Sources
PP2 N/AThe PALB2 expert specification does not use PP2 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PP2 not applicable.
Evidence considered
- PALB2 CSPEC lists PP2 as not applicable.
Sources
PP3 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of >=0.2. REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification states that PP3 should not be applied to missense variants. Details ▾Hide ▴
Rule
PALB2 CSPEC PP3: splicing-only use when SpliceAI >=0.2; do not apply for missense variants.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.449
- BayesDel -0.120213
- PALB2 CSPEC does not apply PP3 to missense variants.
Sources
PP4 N/AThe PALB2 expert specification does not use PP4 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PP4 not applicable.
Evidence considered
- PALB2 CSPEC lists PP4 as not applicable.
Sources
PP5 N/AThe PALB2 expert specification does not use PP5 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: PP5 not applicable.
Evidence considered
- PALB2 CSPEC lists PP5 as not applicable.
Sources
BS3 N/AThe PALB2 expert specification does not use BS3 for this gene, so benign functional evidence was not applied in this framework. Details ▾Hide ▴
Rule
PALB2 CSPEC: BS3 not applicable.
Evidence considered
- PALB2 CSPEC lists BS3 as not applicable.
Sources
BP2 N/AThe PALB2 expert specification does not use BP2 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: BP2 not applicable.
Evidence considered
- PALB2 CSPEC lists BP2 as not applicable.
Sources
BP3 N/AThe PALB2 expert specification does not use BP3 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: BP3 not applicable.
Evidence considered
- PALB2 CSPEC lists BP3 as not applicable.
Sources
BP4 N/ASpliceAI 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, the PALB2 expert specification states that BP4 should not be applied to missense variants. REVEL was 0.449 and BayesDel was -0.120213, but these scores do not override the PALB2 missense rule. Details ▾Hide ▴
Rule
PALB2 CSPEC BP4: splicing-only use when SpliceAI <=0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.449
- BayesDel -0.120213
- PALB2 CSPEC does not apply BP4 to missense variants.
Sources
BP5 N/AThe PALB2 expert specification does not use BP5 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: BP5 not applicable.
Evidence considered
- PALB2 CSPEC lists BP5 as not applicable.
Sources
BP6 N/AThe PALB2 expert specification does not use BP6 for this gene. Details ▾Hide ▴
Rule
PALB2 CSPEC: BP6 not applicable.
Evidence considered
- PALB2 CSPEC lists BP6 as not applicable.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
PALB2 CSPEC BP7: use for synonymous and qualifying deep intronic variants, with optional RNA evidence.
Evidence considered
- NM_024675.3:c.2831T>A predicts p.(Ile944Asn)
- not a synonymous or deep intronic change.
Sources
BS1_supporting_placeholder N/ANo PALB2-specific supporting-level BS1 rule was provided beyond the defined BS1 threshold, so no separate supporting assessment was made. Details ▾Hide ▴
Evidence considered
- Only BS1 strong threshold was specified in the PALB2 CSPEC summary available here.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2831T>A
- Protein (HGVS p.)
- NP_078951.2:p.(Ile944Asn)
- GRCh38
- chr16:23624012 A>T
- GRCh37
- chr16:23635333 A>T
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
3 / 1,577,962 alleles
AF 1.9e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,577,962 alleles · 0 hom · FAF 2.9e-07
| South Asian1 / 90,284 | 1.1e-05 |
| European (non-Finnish)2 / 1,147,306 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.90119e-06; MAF= 0.00019%, 3/1577962 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10762e-05; MAF= 0.00111%, 1/90284 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of >=0.2. REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification states that PP3 should not be applied to missense variants. Details ▾Hide ▴
Rule
PALB2 CSPEC PP3: splicing-only use when SpliceAI >=0.2; do not apply for missense variants.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.449
- BayesDel -0.120213
- PALB2 CSPEC does not apply PP3 to missense variants.
Sources
BP4 N/ASpliceAI 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, the PALB2 expert specification states that BP4 should not be applied to missense variants. REVEL was 0.449 and BayesDel was -0.120213, but these scores do not override the PALB2 missense rule. Details ▾Hide ▴
Rule
PALB2 CSPEC BP4: splicing-only use when SpliceAI <=0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.449
- BayesDel -0.120213
- PALB2 CSPEC does not apply BP4 to missense variants.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
PALB2 CSPEC BP7: use for synonymous and qualifying deep intronic variants, with optional RNA evidence.
Evidence considered
- NM_024675.3:c.2831T>A predicts p.(Ile944Asn)
- not a synonymous or deep intronic change.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.449. BayesDel score = -0.120213.
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
3 / 1,577,962 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/187262/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23635333-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23624012-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2831…
- OncoKB ↗www.oncokb.org/gene/PALB2/I944N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2831T%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= 1.90119e-06; MAF= 0.00019%, 3/1577962 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10762e-05; MAF= 0.00111%, 1/90284 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance 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 = 0.01). REVEL score = 0.449. BayesDel score = -0.120213.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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.