About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2734T>G, p.(Trp912Gly)
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. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 expert-panel specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and true pathogenic missense variants are thought to be very rare. BP1 is met at supporting strength.
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
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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.
28 criteria with recorded statuses: 2 met · 9 not met · 0 not assessed · 17 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.2734T>G (p.Trp912Gly) variant has not been observed in COSMIC and has been reported in ClinVar as Uncertain Significance, including expert-panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333%.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, and although REVEL and BayesDel scores are available, the PALB2 expert-panel specification does not use missense computational predictors for PP3 or BP4.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore below the PALB2 PM2_Supporting threshold of 1 in 300,000 (0.000333%), supporting PM2 at supporting strength. Details ▾Hide ▴
Rule
PALB2 PM2_Supporting: frequency ≤1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1.
- Absent from gnomAD v2.1.
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 expert-panel specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and true pathogenic missense variants are thought to be very rare. BP1 is met at supporting strength. Details ▾Hide ▴
Rule
PALB2 BP1: apply to all missense variants.
Evidence considered
- Variant protein consequence is p.Trp912Gly.
- PALB2 VCEP instructs BP1 for all missense variants.
Sources
Not met · 9 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and SpliceAI does not support a splice-disrupting effect (max delta score 0.03). Available evidence therefore does not support applying PVS1. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; not a default null-variant category for this missense change.
Evidence considered
- PALB2 is eligible for gene-specific PVS1 assessment because loss of function is an established disease mechanism.
- The variant is a missense substitution
- p.Trp912Gly.
- SpliceAI max delta score is 0.03
- below the PALB2 splice-prediction threshold used for PP3 and inconsistent with a predicted splice defect.
Still missing
- No RNA study demonstrating an abnormal splice defect was identified.
Sources
PS4 This variant has been reported in ClinVar, but no case-control study showing significant enrichment in affected individuals was identified. The available evidence does not meet the PALB2 PS4 requirement of p-value less than or equal to 0.05 with an odds ratio, hazard ratio, or relative risk at least 3 or lower 95% confidence interval at least 1.5. Details ▾Hide ▴
Rule
Case-control studies with p≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- ClinVar reports the variant as Uncertain Significance
- including expert-panel review.
- No qualifying case-control statistics were identified.
Still missing
- No variant-specific case-control dataset or quantitative enrichment analysis was identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband meeting the PALB2 Fanconi anemia scoring framework. Available evidence does not support PM3. Details ▾Hide ▴
Rule
Requires PM3 point-based evidence in the PALB2 Fanconi anemia framework.
Evidence considered
- No PM3-qualifying case data were identified.
Still missing
- No phased biallelic observations or PM3 point-based evidence were identified.
Sources
PP1 No segregation data were identified for this variant. Available evidence does not show the quantitative co-segregation required to reach the PALB2 PP1 thresholds. Details ▾Hide ▴
Rule
Requires quantitative co-segregation meeting PALB2 PP1 thresholds.
Evidence considered
- No PP1-qualifying segregation evidence was identified.
Still missing
- No family-based LOD score
- Bayes factor
- or affected-relative segregation data were identified.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 specification does not use missense computational predictors for PP3. Available computational evidence therefore does not support PP3. Details ▾Hide ▴
Rule
PALB2 PP3 uses predicted splice impact only; SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.03.
- REVEL score 0.562.
- BayesDel score 0.00991955.
- PALB2 VCEP states missense predictors should not be used for PP3.
Sources
BA1 This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BA1 threshold of greater than 0.1% filtering allele frequency. BA1 is not met. Details ▾Hide ▴
Rule
PALB2 BA1: grpmax filtering AF >0.1% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v4.1 and therefore is below the PALB2 BS1 threshold of greater than 0.01% filtering allele frequency. BS1 is not met. Details ▾Hide ▴
Rule
PALB2 BS1: grpmax filtering AF >0.01% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1.
Sources
BS2 No evidence was identified that this variant was observed in healthy adults in a configuration that meets the PALB2 BS2 point-based framework. Available evidence does not support BS2. Details ▾Hide ▴
Rule
Requires BS2 point-based evidence in the PALB2 framework.
Evidence considered
- No BS2-qualifying observations were identified.
Still missing
- No qualifying unaffected-adult observations with BS2 point assignment were identified.
Sources
BS4 No non-segregation data were identified for this variant. Available evidence does not show the quantitative lack of segregation required to reach the PALB2 BS4 thresholds. Details ▾Hide ▴
Rule
Requires quantitative lack of segregation meeting PALB2 BS4 thresholds.
Evidence considered
- No BS4-qualifying segregation evidence was identified.
Still missing
- No family-based LOD score or Bayes factor supporting lack of segregation was identified.
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AUnder the PALB2 specification, PS1 is not used for missense changes and is reserved for specific splicing-table scenarios. No PALB2 splicing-table evidence was identified for this variant. Details ▾Hide ▴
Rule
PALB2: missense do not use; splicing only via PALB2 PS1 table.
Evidence considered
- PALB2 VCEP guidance states PS1 should not be used for missense changes.
- SpliceAI does not indicate a meaningful splice effect for this variant.
Sources
PS2 VCEPThe PALB2 specification does not use PS2 for this disease context. No qualifying confirmed de novo evidence was identified. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PS2 as not applicable.
Sources
PS3 VCEPThe PALB2 specification does not use PS3 for protein functional assays, and no RNA evidence was identified that would redirect assessment to a splice-based framework. Available evidence therefore does not support PS3 use in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP; RNA effects would be handled through splice-related rules instead.
Evidence considered
- PALB2 VCEP marks PS3 as not applicable for protein functional evidence.
- SpliceAI predicts no significant splice impact (max delta score 0.03).
Still missing
- No RNA study demonstrating an abnormal splice effect was identified.
Sources
PM1 VCEPThe PALB2 specification does not use PM1 because missense pathogenicity and hotspot/domain-based missense interpretation are not established mechanisms for this gene in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PM1 as not applicable.
Sources
PM4 VCEPPM4 is not applicable because this variant is a missense substitution, not a stop-loss variant or qualifying in-frame length-change variant under the PALB2 specification. Details ▾Hide ▴
VCEP rule
Not applicable for this missense variant.
Evidence considered
- PALB2 VCEP restricts PM4 to stop-loss use.
Sources
PM5 N/AUnder the PALB2 specification, PM5 is not used for missense changes and instead applies only as PM5_Supporting for qualifying truncating or splice variants upstream of p.Tyr1183*. This missense variant does not meet that rule. Details ▾Hide ▴
Rule
PALB2 PM5_Supporting applies to qualifying truncating/splice variants, not missense variants.
Evidence considered
- PM5 candidate review identified a non-classic truncation-cutoff framework and found the variant ineligible for classic same-residue PM5 use.
- The variant is a missense substitution
- p.Trp912Gly.
Sources
cspec ↗pm5_candidates
PM6 VCEPThe PALB2 specification does not use PM6 in this disease context. No assumed de novo evidence relevant to a PALB2 PM6 framework was identified. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PM6 as not applicable.
Sources
PP2 VCEPThe PALB2 specification does not use PP2 because missense variation is not an established pathogenic mechanism in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PP2 as not applicable.
Sources
PP4 VCEPThe PALB2 specification does not use PP4 for the autosomal dominant cancer-predisposition setting because the phenotype is not sufficiently specific to a single genetic cause. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PP4 as not applicable.
Sources
PP5 VCEPPP5 is not used in this PALB2 expert-panel framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks PP5 as not applicable.
Sources
BS3 VCEPThe PALB2 specification does not use BS3 for protein functional assays, and no RNA evidence was identified to support a splice-based benign RNA code. Available evidence therefore does not support BS3 use in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP; RNA effects are handled with BP7-based RNA logic when available.
Evidence considered
- PALB2 VCEP marks BS3 as not applicable for protein functional evidence.
- SpliceAI predicts no significant splice impact
- but no observed RNA study was identified.
Still missing
- No RNA study demonstrating lack of aberrant splicing was identified.
Sources
BP2 VCEPThe PALB2 specification does not use BP2 in this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks BP2 as not applicable.
Sources
BP3 VCEPBP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region without known function. Details ▾Hide ▴
VCEP rule
Not applicable for this missense variant.
Evidence considered
- PALB2 VCEP marks BP3 as not applicable.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 specification states that BP4 should not be applied for missense variants. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 framework does not use missense computational predictors for BP4. Details ▾Hide ▴
Rule
PALB2 BP4: splicing only, SpliceAI ≤0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.03.
- REVEL score 0.562.
- BayesDel score 0.00991955.
- PALB2 VCEP states BP4 should not be applied for missense variants.
Sources
BP5 VCEPBP5 is not used in the PALB2 specification. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks BP5 as not applicable.
Sources
BP6 VCEPBP6 is not used in this PALB2 expert-panel framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 VCEP.
Evidence considered
- PALB2 VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those settings. This variant is a missense substitution and no RNA study showing normal splicing was identified. Details ▾Hide ▴
Rule
PALB2 BP7 applies to synonymous/deep intronic variants or qualifying RNA evidence.
Evidence considered
- Variant protein consequence is p.Trp912Gly.
- SpliceAI predicts no significant splice impact
- but BP7 is not the missense rule in this setting.
Still missing
- No RNA study demonstrating lack of aberrant splicing was identified.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2734T>G
- Protein (HGVS p.)
- NP_078951.2:p.(Trp912Gly)
- GRCh38
- chr16:23626250 A>C
- GRCh37
- chr16:23637571 A>C
- ClinVar
- 3702771, 2498117
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
- 0.562
- BayesDel
- 0.010
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 specification does not use missense computational predictors for PP3. Available computational evidence therefore does not support PP3. Details ▾Hide ▴
Rule
PALB2 PP3 uses predicted splice impact only; SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.03.
- REVEL score 0.562.
- BayesDel score 0.00991955.
- PALB2 VCEP states missense predictors should not be used for PP3.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 specification states that BP4 should not be applied for missense variants. REVEL (0.562) and BayesDel (0.00991955) are available, but the PALB2 framework does not use missense computational predictors for BP4. Details ▾Hide ▴
Rule
PALB2 BP4: splicing only, SpliceAI ≤0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.03.
- REVEL score 0.562.
- BayesDel score 0.00991955.
- PALB2 VCEP states BP4 should not be applied for missense variants.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those settings. This variant is a missense substitution and no RNA study showing normal splicing was identified. Details ▾Hide ▴
Rule
PALB2 BP7 applies to synonymous/deep intronic variants or qualifying RNA evidence.
Evidence considered
- Variant protein consequence is p.Trp912Gly.
- SpliceAI predicts no significant splice impact
- but BP7 is not the missense rule in this setting.
Still missing
- No RNA study demonstrating lack of aberrant splicing was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.562. BayesDel score = 0.00991955.
9 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.No paper-specific finding is recorded.
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PMID 31757951 ↗Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2.Boonen RACM et al. · 2019No paper-specific finding is recorded.
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PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.No 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 0.030
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/2498117/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23637571-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23626250-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2734…
- OncoKB ↗www.oncokb.org/gene/PALB2/W912G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2734T%3EG
- 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 (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 2498117)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.562. BayesDel score = 0.00991955.
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.