About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3132A>T, p.(Gln1044His)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic PALB2 variants are predominantly truncating and true pathogenic missense variants are thought to be very uncommon.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.
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
22 / 1,612,054 alleles
gnomAD v4.1: 22 / 1,612,054 alleles. Recorded AF 1.36472e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96851e-06; MAF= 0.00080%, 2/250988 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.55265e-05; MAF= 0.00655%, 2/30522 alleles, homozygotes = 0); grpmax FAF= 1.085e-05.
No listed criterion applied
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions
5 Uncertain significance.
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: 1 met · 5 not met · 6 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.3132A>T (p.Gln1044His) variant has not been identified as a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance with 5 clinical laboratory submissions.
This variant is present in population databases, including gnomAD v4.1 at 0.00136% overall (22/1612054 alleles) with a highest observed population frequency of 0.00989% in South Asian individuals, which is above the PALB2 PM2_Supporting threshold of 0.000333% but below the BS1 threshold of 0.01% and the BA1 threshold of 0.1%.
Computational evidence does not suggest a splice-disrupting effect, with a SpliceAI maximum delta score of 0.02, and this value is below the PALB2 PP3 splicing threshold of 0.2; additional missense predictor scores were REVEL 0.227 and BayesDel -0.259388.
No criteria match.
Met · 1
BP1 SupportingThis variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic PALB2 variants are predominantly truncating and true pathogenic missense variants are thought to be very uncommon. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- Variant is p.(Gln1044His)
- a missense change.
- PALB2 VCEP instructs BP1 for all missense variants.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and the available splicing data do not show a splice-disrupting effect that would support a PVS1-based loss-of-function interpretation. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; generic scaffold does not place this variant in a nonsense, frameshift, or canonical +/-1,2 splice category.
Evidence considered
- PALB2 is PVS1-eligible at the gene level.
- The variant-level PVS1 scaffold states this variant is not in a default null-variant bucket.
- SpliceAI max delta score is 0.02.
Still missing
- No RNA study for this exact variant was identified.
Sources
PM2 This variant is present in gnomAD v4.1 at 0.00136% (22/1612054 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires frequency <=1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- gnomAD v4.1 total AF is 1.36472e-05 (0.00136%).
- gnomAD v2.1 also shows the variant at low but non-zero frequency.
Sources
PP3 SpliceAI predicts no meaningful splice effect for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
For PALB2, PP3 is used for predicted splicing impact with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score is 0.02.
- REVEL score is 0.227.
- BayesDel score is -0.259388.
Still missing
- No RNA study for this exact variant was identified.
Sources
BA1 The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is well below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires grpmax filtering AF >0.1% in gnomAD v4.
Evidence considered
- gnomAD v4.1 South Asian AF is 9.89402e-05 (0.00989%).
- gnomAD v4.1 total AF is 1.36472e-05.
Sources
BS1 The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires grpmax filtering AF >0.01% in gnomAD v4.
Evidence considered
- gnomAD v4.1 South Asian AF is 9.89402e-05 (0.00989%).
Sources
Not assessed · 6 · no assessment recorded
PS1 No evidence was identified that this variant produces the same established pathogenic protein or splice consequence as a previously classified PALB2 variant, and the specific PALB2 PS1 splicing-table comparison was not available in the retrieved materials. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table.
Evidence considered
- PALB2 PS1 requires use of a gene-specific splicing table.
- ClinVar shows this variant as uncertain significance.
- Available splicing prediction does not suggest a strong splice effect.
Still missing
- No PALB2 PS1 splicing-table match was identified for this variant.
Sources
PS4 This variant has been reported in ClinVar, but no case-control study or exact affected-versus-control enrichment statistic meeting the PALB2 PS4 threshold was identified. Details ▾Hide ▴
Rule
Case-control studies with p<=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5.
Evidence considered
- ClinVar lists the variant as uncertain significance with 5 clinical laboratory submissions.
- No qualifying case-control statistic was identified.
Still missing
- No odds ratio
- relative risk
- hazard ratio
- or lower 95% confidence interval meeting the PALB2 PS4 rule was identified for this exact variant.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an informative Fanconi anemia context, so PM3 could not be assessed. Details ▾Hide ▴
Rule
PALB2 PM3 point-based Fanconi anemia framework.
Evidence considered
- PALB2 PM3 requires point-based proband evidence for recessive disease.
- No such evidence was identified in the retrieved case materials.
Still missing
- No phase-confirmed Fanconi anemia proband data were identified.
Sources
PP1 No segregation data, LOD score, or Bayes factor was identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
Rule
Supporting requires AD LOD >=0.3 or LR >=2:1, or AR segregation in 1 affected relative.
Evidence considered
- PALB2 PP1 requires quantitative co-segregation evidence.
- No pedigree-based evidence was identified in the retrieved materials.
Still missing
- No family-based segregation data were identified.
Sources
BS2 No qualifying observations in unaffected individuals meeting the PALB2 BS2 point-based framework were identified. Details ▾Hide ▴
Rule
PALB2 BS2 point-based unaffected-individual framework.
Evidence considered
- PALB2 BS2 requires point-based unaffected-individual evidence and excludes use of population cohort data such as gnomAD.
Still missing
- No informative unaffected-carrier data were identified.
- Population database observations are not sufficient for PALB2 BS2.
Sources
BS4 No quantitative non-segregation evidence, negative LOD score, or Bayes factor meeting the PALB2 BS4 framework was identified. Details ▾Hide ▴
Rule
Supporting requires LOD <=-0.32 or LR <=0.48; stronger thresholds apply for higher strengths.
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence.
- No such evidence was identified in the retrieved materials.
Still missing
- No family-based non-segregation data were identified.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThe PALB2 specification does not use PS2 for this gene-disease context. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks PS2 as not applicable.
Sources
PS3 VCEPThe PALB2 specification does not use PS3 for this gene, so no pathogenic functional criterion was applied in this review. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks PS3 as not applicable.
Sources
PM1 VCEPThe PALB2 specification does not use PM1 because missense pathogenic variation has not been established as a mechanism suitable for this rule in PALB2. Details ▾Hide ▴
VCEP rule
Do not use for PALB2 missense variants.
Evidence considered
- PALB2 VCEP marks PM1 as not applicable.
- No hotspot row was identified for this residue.
Sources
PM4 VCEPThis is a missense substitution, and the PALB2 specification limits PM4 to stop-loss variants rather than missense changes. Details ▾Hide ▴
VCEP rule
Use for stop-loss variants only.
Evidence considered
- Variant is p.(Gln1044His).
- PALB2 VCEP marks PM4 not applicable except for stop-loss use.
Sources
PM5 N/AThe PALB2 PM5 rule is a truncation-cutoff framework and does not apply to this missense variant. Details ▾Hide ▴
Rule
Apply to truncating variants with premature termination codons upstream of p.Tyr1183, or qualifying NMD-prone splice variants.
Evidence considered
- PM5 candidate review identified a truncation-cutoff gene-specific rule rather than classic same-residue missense PM5.
- The variant is missense
- not truncating or qualifying splice.
Sources
cspec ↗pm5_candidates
PM6 VCEPThe PALB2 specification does not use PM6 for this gene-disease context. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks PM6 as not applicable.
Sources
PP2 VCEPThe PALB2 specification does not use PP2 because missense variation has not been established as a suitable mechanism for this criterion in PALB2. Details ▾Hide ▴
VCEP rule
Do not use for PALB2 missense variants.
Evidence considered
- PALB2 VCEP marks PP2 as not applicable.
Sources
PP4 VCEPThe PALB2 specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for this criterion. Details ▾Hide ▴
VCEP rule
Do not use for AD PALB2-related cancer predisposition.
Evidence considered
- PALB2 VCEP marks PP4 as not applicable.
Sources
PP5 VCEPThe PALB2 specification does not use PP5. Details ▾Hide ▴
BS3 VCEPThe PALB2 specification does not use BS3 for this gene. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks BS3 as not applicable.
Sources
BP2 VCEPThe PALB2 specification does not use BP2 for this gene-disease context. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks BP2 as not applicable.
Sources
BP3 VCEPThe PALB2 specification does not use BP3 for this gene. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks BP3 as not applicable.
Sources
BP4 N/AAlthough SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applied here. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI <=0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.02.
- PALB2 BP4 guidance states not to apply BP4 for missense variants.
Still missing
- No RNA study for this exact variant was identified.
Sources
BP5 VCEPThe PALB2 specification does not use BP5 for this gene-disease context. Details ▾Hide ▴
VCEP rule
Do not use for PALB2.
Evidence considered
- PALB2 VCEP marks BP5 as not applicable.
Sources
BP6 VCEPThe PALB2 specification does not use BP6. Details ▾Hide ▴
BP7 N/AThis criterion is intended for synonymous or deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA-based lack of splice defect in those contexts.
Evidence considered
- Variant is p.(Gln1044His)
- a missense change.
- PALB2 BP7 guidance is for synonymous and deep intronic variants.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.3132A>T
- Protein (HGVS p.)
- NP_078951.2:p.(Gln1044His)
- GRCh38
- chr16:23614073 T>A
- GRCh37
- chr16:23625394 T>A
- ClinVar
- 460977
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PALB2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
22 / 1,612,054 alleles
AF 1.36e-05 · 0 homozygotes · FAF 5.14e-05
gnomAD v2.1
2 / 250,988 alleles
AF 7.97e-06 · 0 homozygotes · FAF 1.08e-05
By genetic ancestry
gnomAD v4.1
AF 1.4e-05 · 22 / 1,612,054 alleles · 0 hom · FAF 5.1e-05
| South Asian9 / 90,964 | 9.9e-05 |
| European (non-Finnish)13 / 1,178,492 | 1.1e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 250,988 alleles · 0 hom · FAF 1.1e-05
| South Asian2 / 30,522 | 6.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.36472e-05; MAF= 0.00136%, 22/1612054 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.89402e-05; MAF= 0.00989%, 9/90964 alleles, homozygotes = 0); grpmax FAF= 5.143e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96851e-06; MAF= 0.00080%, 2/250988 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.55265e-05; MAF= 0.00655%, 2/30522 alleles, homozygotes = 0); grpmax FAF= 1.085e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.227
- BayesDel
- -0.259
How the predictions were used
PP3 SpliceAI predicts no meaningful splice effect for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
For PALB2, PP3 is used for predicted splicing impact with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score is 0.02.
- REVEL score is 0.227.
- BayesDel score is -0.259388.
Still missing
- No RNA study for this exact variant was identified.
Sources
BP4 N/AAlthough SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applied here. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI <=0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.02.
- PALB2 BP4 guidance states not to apply BP4 for missense variants.
Still missing
- No RNA study for this exact variant was identified.
Sources
BP7 N/AThis criterion is intended for synonymous or deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA-based lack of splice defect in those contexts.
Evidence considered
- Variant is p.(Gln1044His)
- a missense change.
- PALB2 BP7 guidance is for synonymous and deep intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.227. BayesDel score = -0.259388.
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
-
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.
-
PMID 31636395 ↗Functional characterization of 84 PALB2 variants of uncertain significance.Wiltshire T et al. · 2020No paper-specific finding is recorded.
-
PMID 33811135 ↗Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore.Ng PS et al. · 2022No paper-specific finding is recorded.
-
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.
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.No paper-specific finding is recorded.
-
PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.No paper-specific finding is recorded.
-
PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.No paper-specific finding is recorded.
-
PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
-
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
22 / 1,612,054 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
5 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/460977/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23625394-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23614073-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.3132…
- OncoKB ↗www.oncokb.org/gene/PALB2/Q1044H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.3132A%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
This variant is present in gnomAD v4.1 (AF= 1.36472e-05; MAF= 0.00136%, 22/1612054 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.89402e-05; MAF= 0.00989%, 9/90964 alleles, homozygotes = 0); grpmax FAF= 5.143e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96851e-06; MAF= 0.00080%, 2/250988 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.55265e-05; MAF= 0.00655%, 2/30522 alleles, homozygotes = 0); grpmax FAF= 1.085e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 460977)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.227. BayesDel score = -0.259388.
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.