About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.338C>T, p.(Pro113Leu)
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 and gnomAD v2.1. The observed frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variants in PALB2 are thought to be exceedingly rare. BP1_Supporting is met.
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: PM2 supporting, BP1 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Uncertain significance · 1 Likely benign.
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
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 · 3 not met · 5 not assessed · 18 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.338C>T (p.Pro113Leu) variant has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as uncertain significance, with additional submissions of uncertain significance and likely benign.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed frequency below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).
SpliceAI predicts no splice impact with a max delta score of 0.00, and missense predictors are low (REVEL 0.012; BayesDel -0.722131); however, the PALB2 expert specification does not use PP3 or BP4 for missense prediction and applies BP1_Supporting to all missense variants.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met. Details ▾Hide ▴
Rule
PM2_Supporting when frequency ≤ 1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- PALB2 VCEP PM2 threshold ≤0.000333%
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variants in PALB2 are thought to be exceedingly rare. BP1_Supporting is met. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- Variant is missense p.Pro113Leu
- PALB2 VCEP BP1 applies to all missense variants
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 This missense variant does not meet PALB2 PVS1 criteria. PALB2 loss of function is an established disease mechanism, but c.338C>T (p.Pro113Leu) is not a nonsense, frameshift, or canonical ±1,2 splice variant, and SpliceAI predicts no splice effect (max delta score 0.00), so the available evidence does not support a PVS1-based loss-of-function classification. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- PALB2 VCEP PVS1 decision-tree framework applies to loss-of-function or qualifying splice variants
- PALB2 is eligible for PVS1 at the gene level
- c.338C>T is a missense change outside the default generic PVS1 null-variant categories
- SpliceAI max delta score 0.00
Sources
BA1 This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BA1 threshold of greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.1% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1
- BA1 threshold >0.1%
Sources
BS1 This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BS1 threshold of greater than 0.01%. BS1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.01% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1
- BS1 threshold >0.01%
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, including an expert panel uncertain significance classification, but no case-control study or exact-variant enrichment data were identified to show a statistically significant increase in affected individuals. Therefore PS4 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- ClinVar expert panel VUS submission present
- No exact-variant case-control data identified
Still missing
- No exact-variant odds ratio
- relative risk
- or lower 95% confidence interval was identified.
- No case-control p-value for this exact variant was identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a Fanconi anemia context, and no PM3 point-based proband data were available. PM3 is not applied. Details ▾Hide ▴
Rule
Apply by Fanconi anemia PM3 point system.
Evidence considered
- PALB2 VCEP PM3 requires point-based trans observations
Still missing
- No phase-confirmed in trans observation was identified.
- No Fanconi anemia proband point data were identified.
Sources
PP1 No segregation data were identified for this variant, and no LOD score, Bayes factor, or affected-relative count was available to meet PALB2 PP1 thresholds. PP1 is not applied. Details ▾Hide ▴
Rule
Apply by PALB2 co-segregation thresholds using LOD/Bayes factor or affected-relative counts.
Evidence considered
- PALB2 VCEP PP1 requires quantitative segregation evidence
- No segregation detail identified in reviewed materials
Still missing
- No quantitative segregation data were identified.
- No affected-relative count or LOD score was identified.
Sources
BS2 No evidence was identified that this variant was observed in healthy individuals under the PALB2 BS2 point-based framework, and population database absence cannot be used for BS2. BS2 is not applied. Details ▾Hide ▴
Rule
Apply by Fanconi anemia BS2 point system; do not use population cohorts such as gnomAD.
Evidence considered
- PALB2 VCEP BS2 requires point-based healthy observations and excludes use of population cohorts such as gnomAD
- Variant absent from gnomAD
Still missing
- No qualifying healthy adult observations were identified.
- No BS2 point-based proband data were identified.
Sources
BS4 No non-segregation data, negative LOD score, or Bayes factor was identified for this variant. Therefore BS4 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Apply by PALB2 non-segregation thresholds using LOD or Bayes factor.
Evidence considered
- PALB2 VCEP BS4 requires quantitative non-segregation evidence
- No family non-segregation details identified
Still missing
- No formal non-segregation analysis was identified.
- No unaffected-carrier or discordant family data were identified.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion is not applied for this missense variant because the PALB2 expert specification states that PS1 should not be used for missense changes and instead reserves PS1 for qualifying splice comparisons. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: See PALB2 PS1 Table.
Evidence considered
- PALB2 VCEP PS1 guidance: missense do not use
- splicing table only
Sources
PS2 VCEPThis criterion is not applicable because the PALB2 expert specification does not use de novo evidence for PALB2 autosomal dominant or autosomal recessive disease assessment. Details ▾Hide ▴
VCEP rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP PS2 guidance: do not use
Sources
PS3 VCEPThis criterion is not applicable in the PALB2 expert framework. No variant-specific functional study was identified that would override this specification for protein-level PS3 use. Details ▾Hide ▴
PM1 VCEPThis criterion is not applicable because the PALB2 expert specification does not use PM1; missense pathogenic variation in PALB2 is not yet established as a disease mechanism, and no hotspot evidence supports this residue. Details ▾Hide ▴
VCEP rule
Do not use: missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
Evidence considered
- PALB2 VCEP PM1 marked not applicable
- No statistically significant hotspot identified
Sources
PM4 VCEPThis criterion is not applicable because c.338C>T is a missense substitution, not a stop-loss variant, and the PALB2 expert specification limits PM4 use to stop-loss variants. Details ▾Hide ▴
VCEP rule
Use for stop-loss variants only.
Evidence considered
- Variant is missense
- PALB2 VCEP PM4 limited to stop-loss
Sources
PM5 N/AThis criterion is not applied for this variant. In PALB2, PM5 is repurposed for qualifying truncating or splice variants upstream of p.Tyr1183 and is specifically not used for missense changes such as p.Pro113Leu. Details ▾Hide ▴
Rule
Do not use for missense changes; PM5_Supporting only for qualifying truncating or splice variants.
Evidence considered
- PALB2 VCEP PM5 excludes missense variants
- PM5 candidate review indicates non-classic truncation-cutoff framework
Sources
cspec ↗pm5_candidates
PM6 VCEPThis criterion is not applicable because the PALB2 expert specification does not use assumed de novo evidence for PALB2 disease assessment. Details ▾Hide ▴
VCEP rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP PM6 marked not applicable
Sources
PP2 VCEPThis criterion is not applicable because the PALB2 expert specification does not use PP2; missense variation is not an established PALB2 disease mechanism for this purpose. Details ▾Hide ▴
PP3 N/AThis criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 PP3 splice threshold of 0.2), and the PALB2 expert specification states that PP3 should not be used for missense prediction. REVEL is 0.012 and BayesDel is -0.722131, but these missense predictor results do not support PP3 use in this framework. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.012
- BayesDel score -0.722131
- PALB2 VCEP PP3: missense do not use
- splicing threshold ≥0.2
Sources
PP4 VCEPThis criterion is not applicable because the PALB2 expert specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition, as the phenotype is not sufficiently specific to PALB2 alone. Details ▾Hide ▴
VCEP rule
Do not use for AD disorder.
Evidence considered
- PALB2 VCEP PP4 marked not applicable
Sources
PP5 VCEPThis criterion is not applicable because PP5 is not used by the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not for use as recommended by the VCEP.
Evidence considered
- PALB2 VCEP PP5 marked not applicable
Sources
BS3 VCEPThis criterion is not applicable in the PALB2 expert framework for this variant, and no variant-specific benign functional study was identified for an alternate approved route to use. Details ▾Hide ▴
VCEP rule
Not applicable in this PALB2 VCEP framework.
Evidence considered
- PALB2 VCEP BS3 marked not applicable
- No variant-specific reviewed functional evidence identified in OncoKB
Sources
BP2 VCEPThis criterion is not applicable because the PALB2 expert specification does not use BP2 in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in this PALB2 VCEP framework.
Evidence considered
- PALB2 VCEP BP2 marked not applicable
Sources
BP3 VCEPThis criterion is not applicable because c.338C>T is not an in-frame insertion or deletion, and the PALB2 expert specification does not use BP3 for PALB2. Details ▾Hide ▴
VCEP rule
Do not use.
Evidence considered
- Variant is missense
- PALB2 VCEP BP3 marked not applicable
Sources
BP4 N/AThis criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 BP4 splice threshold of 0.1), and REVEL (0.012) and BayesDel (-0.722131) are low, but the PALB2 expert specification states that BP4 should not be used for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≤0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.012
- BayesDel score -0.722131
- PALB2 VCEP BP4: missense do not use
- splicing only if SpliceAI ≤0.1
Sources
BP5 VCEPThis criterion is not applicable because the PALB2 expert specification does not use BP5. Details ▾Hide ▴
BP6 VCEPThis criterion is not applicable because BP6 is not used by the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not for use as recommended by the VCEP.
Evidence considered
- PALB2 VCEP BP6 marked not applicable
Sources
BP7 N/AThis criterion is not applicable because c.338C>T is a missense variant rather than a synonymous or deep intronic variant, which are the variant types addressed by PALB2 BP7. Details ▾Hide ▴
Rule
Use for synonymous and qualifying deep intronic variants or RNA evidence showing no splice defect.
Evidence considered
- Variant is missense
- PALB2 VCEP BP7 intended for synonymous and deep intronic variants
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.338C>T
- Protein (HGVS p.)
- NP_078951.2:p.(Pro113Leu)
- GRCh38
- chr16:23636208 G>A
- GRCh37
- chr16:23647529 G>A
- ClinVar
- 492220
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
- 0.012
- BayesDel
- -0.722
How the predictions were used
PP3 N/AThis criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 PP3 splice threshold of 0.2), and the PALB2 expert specification states that PP3 should not be used for missense prediction. REVEL is 0.012 and BayesDel is -0.722131, but these missense predictor results do not support PP3 use in this framework. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.012
- BayesDel score -0.722131
- PALB2 VCEP PP3: missense do not use
- splicing threshold ≥0.2
Sources
BP4 N/AThis criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 BP4 splice threshold of 0.1), and REVEL (0.012) and BayesDel (-0.722131) are low, but the PALB2 expert specification states that BP4 should not be used for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≤0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.012
- BayesDel score -0.722131
- PALB2 VCEP BP4: missense do not use
- splicing only if SpliceAI ≤0.1
Sources
BP7 N/AThis criterion is not applicable because c.338C>T is a missense variant rather than a synonymous or deep intronic variant, which are the variant types addressed by PALB2 BP7. Details ▾Hide ▴
Rule
Use for synonymous and qualifying deep intronic variants or RNA evidence showing no splice defect.
Evidence considered
- Variant is missense
- PALB2 VCEP BP7 intended for synonymous and deep intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.012. BayesDel score = -0.722131.
2 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 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No 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 0.000
Open source ↗
ClinVar
1 Uncertain significance · 1 Likely benign
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/492220/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647529-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23636208-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.338C…
- OncoKB ↗www.oncokb.org/gene/PALB2/P113L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.338C%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 (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 492220)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.012. BayesDel score = -0.722131.
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.