About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3089C>T, p.(Thr1030Ile)
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 v4.1, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This is a missense variant, and the PALB2 expert specification directs BP1 to be applied 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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
4 reported laboratory submissions
4 Uncertain significance.
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
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: 2 met · 5 not met · 5 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.3089C>T (p.Thr1030Ile) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current overall interpretation is uncertain significance, including an expert panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its population frequency is therefore below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 thresholds.
In published functional studies, p.(Thr1030Ile) showed abnormal behavior in PALB2 DNA-repair assays, including protein instability, altered interactions within the BRCA2/RAD51C repair complex, marked homologous recombination defects, impaired recruitment to DNA damage sites, cytoplasmic accumulation, and increased PARP inhibitor sensitivity, consistent with a damaging effect.
SpliceAI 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 is 0.434 and BayesDel is -0.0862002, but the PALB2 expert specification does not use missense in silico scores for PP3/BP4 adjudication.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. 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
- PALB2 PM2_Supporting threshold ≤0.000333% in gnomAD v4
Sources
BP1 SupportingThis is a missense variant, and the PALB2 expert specification directs BP1 to be applied to all missense variants. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant consequence p.(Thr1030Ile)
- PALB2 BP1 applies to all missense variants
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1,2 splice variant, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. Available evidence does not support a loss-of-function or RNA-null mechanism for this variant, so PVS1 is not applied. Details ▾Hide ▴
Rule
Use PALB2 PVS1 decision tree
Evidence considered
- PALB2 LoF mechanism supported
- Generic PVS1 scaffold says variant is outside default null buckets
- SpliceAI max delta 0.01
Still missing
- No variant-specific RNA evidence demonstrating an abnormal null-producing splice effect was identified.
Sources
PS1 No evidence was identified that this variant has the same established splicing consequence as a previously classified pathogenic PALB2 variant, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table
Evidence considered
- PALB2 PS1 uses a splicing table
- SpliceAI max delta 0.01
- No matching splice comparator identified
Still missing
- No PALB2 PS1 splicing-table match was identified.
Sources
PP3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of ≥0.2. Details ▾Hide ▴
Rule
Splicing predicted impact via SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.434
- BayesDel -0.0862002
- PALB2 PP3 uses splicing prediction rather than missense in silico scoring
Sources
BA1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
- PALB2 BA1 threshold >0.1% in gnomAD v4
Sources
BS1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
- PALB2 BS1 threshold >0.01% in gnomAD v4
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control dataset, affected-case count, or odds ratio meeting the PALB2 PS4 threshold was identified. Details ▾Hide ▴
Rule
Case-control studies with p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5
Evidence considered
- ClinVar reports the variant
- No qualifying PS4 statistical evidence identified
Still missing
- No case-control analysis with p-value ≤0.05 and risk estimate ≥3 or lower 95% CI ≥1.5 was identified.
Sources
PM3 No proband data were identified showing this variant in trans with a pathogenic PALB2 variant in a recessive Fanconi anemia context, so PM3 cannot be assigned. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so there is no LOD score or Bayes factor to support PP1. Details ▾Hide ▴
Rule
AD condition requires LOD ≥0.3 or Bayes factor ≥2:1 for PP1_Supporting, with higher thresholds for stronger levels
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence
- No qualifying family data identified
Still missing
- No informative family segregation data were identified.
Sources
BS2 No data were identified showing this variant in unaffected individuals with enough PALB2 BS2 point-based evidence to reach the required threshold. Details ▾Hide ▴
BS4 No segregation study was identified showing lack of segregation with a LOD score or Bayes factor low enough to meet PALB2 BS4. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes factor ≤0.053:1 for BS4_Strong; lower tiers also require quantitative evidence
Evidence considered
- PALB2 BS4 requires quantitative nonsegregation evidence
- No qualifying family data identified
Still missing
- No family-level nonsegregation data with LOD or Bayes factor were identified.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPPS2 is not used in this PALB2 expert specification. Details ▾Hide ▴
PS3 VCEPPS3 is not used in this PALB2 expert specification, even though published functional studies have reported damaging effects for p.(Thr1030Ile). Details ▾Hide ▴
Evidence considered
- PALB2 CSPEC marks PS3 not applicable
- Functional studies describe abnormal protein behavior and DNA repair defects
Sources
PM1 VCEPPM1 is not used in this PALB2 expert specification, and this variant was not identified in a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- PALB2 CSPEC marks PM1 not applicable
- No hotspot row found for T1030
Sources
PM4 VCEPPM4 is not applicable because this variant is a missense substitution rather than a stop-loss or an eligible in-frame length-changing variant under the PALB2 specification. Details ▾Hide ▴
PM5 N/AIn the PALB2 expert specification, PM5 is a truncation-cutoff rule for frameshifting, truncating, or qualifying splice variants upstream of p.Tyr1183, not a same-residue missense rule. This missense variant does not fit that framework. Details ▾Hide ▴
Rule
Apply to truncating or qualifying splice variants upstream of p.Tyr1183
Evidence considered
- PALB2 PM5 is truncation-cutoff gene-specific
- pm5_candidates artifact marked classic same-residue PM5 ineligible
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in this PALB2 expert specification. Details ▾Hide ▴
PP2 VCEPPP2 is not used in this PALB2 expert specification. Details ▾Hide ▴
PP4 VCEPPP4 is not used in this PALB2 expert specification. Details ▾Hide ▴
PP5 VCEPPP5 is not used in current expert-based variant interpretation. Details ▾Hide ▴
BS3 VCEPBS3 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP2 VCEPBP2 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP3 VCEPBP3 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP4 N/AFor PALB2, BP4 is not applied to missense variants. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the expert specification states not to use BP4 for missense variants. Details ▾Hide ▴
Rule
Missense: do not use; splicing no impact via SpliceAI ≤0.1, but do not apply for missense variants
Evidence considered
- Missense variant p.(Thr1030Ile)
- SpliceAI max delta 0.01
- PALB2 BP4 do not apply for missense variants
Sources
BP5 VCEPBP5 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP6 VCEPBP6 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP7 N/AThis criterion is intended for synonymous and specified intronic variants, whereas this variant is missense. Details ▾Hide ▴
Evidence considered
- Variant consequence p.(Thr1030Ile)
- PALB2 BP7 scope is synonymous/deep intronic or RNA-normal silent/intronic variants
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.3089C>T
- Protein (HGVS p.)
- NP_078951.2:p.(Thr1030Ile)
- GRCh38
- chr16:23621386 G>A
- GRCh37
- chr16:23632707 G>A
- ClinVar
- 232977
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.434
- BayesDel
- -0.086
How the predictions were used
PP3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of ≥0.2. Details ▾Hide ▴
Rule
Splicing predicted impact via SpliceAI ≥0.2
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.434
- BayesDel -0.0862002
- PALB2 PP3 uses splicing prediction rather than missense in silico scoring
Sources
BP4 N/AFor PALB2, BP4 is not applied to missense variants. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the expert specification states not to use BP4 for missense variants. Details ▾Hide ▴
Rule
Missense: do not use; splicing no impact via SpliceAI ≤0.1, but do not apply for missense variants
Evidence considered
- Missense variant p.(Thr1030Ile)
- SpliceAI max delta 0.01
- PALB2 BP4 do not apply for missense variants
Sources
BP7 N/AThis criterion is intended for synonymous and specified intronic variants, whereas this variant is missense. Details ▾Hide ▴
Evidence considered
- Variant consequence p.(Thr1030Ile)
- PALB2 BP7 scope is synonymous/deep intronic or RNA-normal silent/intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.434. BayesDel score = -0.0862002.
8 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 24141787 ↗Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.Park JY et al. · 2014No paper-specific finding is recorded.
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PMID 17200672 ↗Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.No paper-specific finding is recorded.
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PMID 19584259 ↗PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2.No paper-specific finding is recorded.
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PMID 19737859 ↗Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
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PMID 31586400 ↗A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.Rodrigue A et al. · 2019No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
4 Uncertain significance
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/232977/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23632707-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23621386-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.3089…
- OncoKB ↗www.oncokb.org/gene/PALB2/T1030I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.3089C%3ET
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 232977)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.434. BayesDel score = -0.0862002.
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.