About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.871G>A, p.(Ala291Thr)
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 (0/1613968 alleles, AF 0%), which is 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 is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants, so 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
0 / 1,613,968 alleles
gnomAD v4.1: 0 / 1,613,968 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251366 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16244 alleles, homozygotes = 0).
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
4 reported laboratory submissions
3 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 · 4 not met · 5 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 NM_024675.3:c.871G>A (NP_078951.2:p.(Ala291Thr), p.(A291T)) variant has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel classified it as uncertain significance.
This variant is absent from gnomAD v4.1 (0/1613968 alleles; AF 0%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and far below the BS1 and BA1 benign frequency thresholds.
SpliceAI predicts no significant splice impact (max delta score 0.00), and available computational scores are low for missense deleteriousness (REVEL 0.068; BayesDel -0.616818); under the PALB2 specification, PP3 and BP4 are not used for missense variants, while BP1 applies to all missense variants.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 (0/1613968 alleles, AF 0%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met. Details ▾Hide ▴
Rule
PM2_Supporting if frequency <=1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- gnomAD v4.1 total AC 0 / AN 1613968
- AF 0.0%.
- PALB2 PM2 threshold is <=1/300
- 000 (0.000333%) in gnomAD v4.
Sources
BP1 SupportingThis is a missense variant, and the PALB2 specification applies BP1_Supporting to all missense variants, so BP1 is met at supporting strength. Details ▾Hide ▴
Rule
BP1_Supporting for all missense variants.
Evidence considered
- Variant consequence is missense: p.(Ala291Thr)/p.(A291T).
- PALB2 BP1 rule: apply to all missense variants.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function PVS1 framework, and SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not supported. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; generic PVS1 scaffold does not apply to this missense variant.
Evidence considered
- PALB2 loss of function is an established disease mechanism in the PALB2 CSPEC framework.
- NM_024675.3:c.871G>A is a missense change p.(Ala291Thr)/p.(A291T)
- not a truncating or canonical +/-1
- 2 splice variant.
- SpliceAI max delta score is 0.00.
Still missing
- No RNA study for this exact variant was identified.
Sources
PS1 No evidence was identified that this variant produces the same RNA effect as an established pathogenic PALB2 variant, and no splice effect is predicted, so PS1 is not supported. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table.
Evidence considered
- PALB2 PS1 is specified through a splicing table.
- SpliceAI max delta score is 0.00.
Still missing
- No PALB2 PS1 splicing-table comparator for this exact variant was identified.
Sources
BA1 This variant is absent from gnomAD v4.1 (AF 0%), which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 if grpmax filtering AF >0.1% in gnomAD v4.
Evidence considered
- gnomAD v4.1 AF 0.0%.
- PALB2 BA1 threshold is >0.1% in gnomAD v4.
Sources
BS1 This variant is absent from gnomAD v4.1 (AF 0%), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 if grpmax filtering AF >0.01% in gnomAD v4.
Evidence considered
- gnomAD v4.1 AF 0.0%.
- PALB2 BS1 threshold is >0.01% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 No case-control study or exact-variant enrichment data were identified to show that this variant is significantly more common in affected individuals than in controls, so PS4 cannot be applied. Details ▾Hide ▴
Rule
Case-control studies; p<=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5.
Evidence considered
- PALB2 PS4 requires case-control evidence with p<=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5.
- The variant is absent from gnomAD v4.1.
- ClinVar shows expert-panel VUS classification but no usable case-control evidence.
Still missing
- No exact-variant odds ratio or case-control dataset was identified.
Sources
PM3 No report was identified showing this variant in trans with a pathogenic PALB2 variant in a recessive Fanconi anemia context, so PM3 cannot be applied. Details ▾Hide ▴
Rule
Use PALB2/Fanconi anemia PM3 point system.
Evidence considered
- PALB2 PM3 requires point-based recessive evidence.
- No exact-variant trans observation was identified in the reviewed materials.
Still missing
- No phase-confirmed biallelic PALB2 case for this exact variant was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
BS2 No point-based evidence in unaffected individuals was identified for this variant, so BS2 cannot be applied. Details ▾Hide ▴
BS4 No non-segregation data or quantitative evidence against cosegregation were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Apply only with PALB2 quantitative non-segregation thresholds.
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence.
- No informative non-segregation data were identified.
Still missing
- No pedigree with LOD<=-0.32 or equivalent Bayes factor was identified.
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThe PALB2 specification does not use PS2 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PS2 as not applicable.
Sources
PS3 VCEPThe PALB2 specification does not use PS3 in this framework, and no variant-specific functional assay evidence was identified. Details ▾Hide ▴
PM1 VCEPThe PALB2 specification does not use PM1 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PM1 as not applicable.
Sources
PM4 VCEPThis is a missense substitution, and the PALB2 specification does not apply PM4 to this variant type. Details ▾Hide ▴
VCEP rule
Not applicable for this missense variant under PALB2 CSPEC.
Evidence considered
- PALB2 PM4 is not applicable except for specified stop-loss use.
Sources
PM5 N/AFor PALB2, PM5 is a truncation-cutoff rule rather than classic same-residue missense logic, so this missense variant does not meet the PALB2 PM5 framework. Details ▾Hide ▴
Rule
PALB2 PM5 applies to specified truncating/splice variants upstream of p.Tyr1183.
Evidence considered
- PM5 candidate review indicates PALB2 uses truncation-cutoff/non-missense PM5 logic.
- This variant is a missense change p.(Ala291Thr).
Sources
cspec ↗pm5_candidates
PM6 VCEPThe PALB2 specification does not use PM6 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PM6 as not applicable.
Sources
PP2 VCEPThe PALB2 specification does not use PP2 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PP2 as not applicable.
Sources
PP3 N/AFor PALB2 missense variants, PP3 is not used. In addition, SpliceAI predicts no significant splice impact (max delta score 0.00, below the 0.2 threshold). Details ▾Hide ▴
Rule
Missense: do not use; splicing PP3 only if SpliceAI >=0.2.
Evidence considered
- PALB2 PP3 rule states missense: do not use.
- SpliceAI max delta score is 0.00.
Sources
PP4 VCEPThe PALB2 specification does not use PP4 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PP4 as not applicable.
Sources
PP5 VCEPThe PALB2 specification does not use PP5 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists PP5 as not applicable.
Sources
BS3 VCEPThe PALB2 specification does not use BS3 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists BS3 as not applicable.
Sources
BP2 VCEPThe PALB2 specification does not use BP2 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists BP2 as not applicable.
Sources
BP3 VCEPThe PALB2 specification does not use BP3 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists BP3 as not applicable.
Sources
BP4 N/AFor PALB2 missense variants, BP4 is not used. SpliceAI also predicts no significant splice impact (max delta score 0.00, below the 0.1 threshold for splicing BP4). Details ▾Hide ▴
Rule
Missense: do not use; splicing BP4 only if SpliceAI <=0.1.
Evidence considered
- PALB2 BP4 rule states missense: do not use.
- SpliceAI max delta score is 0.00.
Sources
BP5 VCEPThe PALB2 specification does not use BP5 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists BP5 as not applicable.
Sources
BP6 VCEPThe PALB2 specification does not use BP6 for this framework. Details ▾Hide ▴
VCEP rule
Not applicable in PALB2 CSPEC.
Evidence considered
- PALB2 CSPEC lists BP6 as not applicable.
Sources
BP7 N/AThis is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous/deep intronic contexts, not this missense variant.
Evidence considered
- PALB2 BP7 is specified for synonymous/deep intronic variants and RNA-negative silent/intronic variants.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.871G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Ala291Thr)
- GRCh38
- chr16:23635675 C>T
- GRCh37
- chr16:23646996 C>T
- ClinVar
- 3393439, 241572
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
0 / 1,613,968 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
0 / 251,366 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,613,968 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD v2.1
AF 0 · 0 / 251,366 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613968 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75000 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251366 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16244 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.068
- BayesDel
- -0.617
How the predictions were used
PP3 N/AFor PALB2 missense variants, PP3 is not used. In addition, SpliceAI predicts no significant splice impact (max delta score 0.00, below the 0.2 threshold). Details ▾Hide ▴
Rule
Missense: do not use; splicing PP3 only if SpliceAI >=0.2.
Evidence considered
- PALB2 PP3 rule states missense: do not use.
- SpliceAI max delta score is 0.00.
Sources
BP4 N/AFor PALB2 missense variants, BP4 is not used. SpliceAI also predicts no significant splice impact (max delta score 0.00, below the 0.1 threshold for splicing BP4). Details ▾Hide ▴
Rule
Missense: do not use; splicing BP4 only if SpliceAI <=0.1.
Evidence considered
- PALB2 BP4 rule states missense: do not use.
- SpliceAI max delta score is 0.00.
Sources
BP7 N/AThis is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous/deep intronic contexts, not this missense variant.
Evidence considered
- PALB2 BP7 is specified for synonymous/deep intronic variants and RNA-negative silent/intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.068. BayesDel score = -0.616818.
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 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.Moyer VA et al. · 2014No paper-specific finding is recorded.
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PMID 24366402 ↗Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.2014No 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
0 / 1,613,968 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 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/241572/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646996-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635675-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.871G…
- OncoKB ↗www.oncokb.org/gene/PALB2/A291T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.871G%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= 0; MAF= 0.00000%, 0/1613968 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75000 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251366 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16244 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) 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 = 241572)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.068. BayesDel score = -0.616818.
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.