About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3054G>C, p.(Glu1018Asp)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant is present in gnomAD v4.1 with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%) and grpmax FAF 0.36785%, both above the PALB2 BA1 threshold of >0.1%. This population frequency supports BA1.
BP1Supporting
BP1 · supporting
This variant is a missense substitution, and the PALB2 specification states that BP1 applies to all missense variants. This supports BP1.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP1 supporting, BP6 supporting benign; maps to Benign.
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
214 / 1,614,106 alleles
gnomAD v4.1: 214 / 1,614,106 alleles. Recorded AF 0.000132581. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000385363; MAF= 0.03854%, 109/282850 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00526263; MAF= 0.52626%, 105/19952 alleles, homozygotes = 0); grpmax FAF= 0.00444365.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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: 3 met · 4 not met · 6 not assessed · 15 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.3054G>C (p.Glu1018Asp; E1018D) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.
This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%), which is above the PALB2 BA1 threshold of 0.1%.
SpliceAI predicts no significant splice effect (max delta score 0.01), below the PALB2 PP3 splice threshold of 0.2; REVEL is 0.118 and BayesDel is -0.42024, and the PALB2 specification does not support missense PP3/BP4 use beyond its stated splice rules.
No criteria match.
Met · 3
BA1 Stand aloneThis variant is present in gnomAD v4.1 with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%) and grpmax FAF 0.36785%, both above the PALB2 BA1 threshold of >0.1%. This population frequency supports BA1. Details ▾Hide ▴
Rule
Grpmax filtering AF >0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 East Asian AF is 0.00416704.
- gnomAD v4.1 grpmax FAF is 0.00367847.
Sources
BP1 SupportingThis variant is a missense substitution, and the PALB2 specification states that BP1 applies to all missense variants. This supports BP1. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- The variant is p.(Glu1018Asp)
- a missense change.
- PALB2 BP1 applies to all missense variants.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1,2 splice variant, and no RNA evidence was identified to show a loss-of-function splicing effect. Available evidence therefore does not support PVS1 for this PALB2 variant. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; missense variant without demonstrated loss-of-function splicing effect does not meet PVS1.
Evidence considered
- PALB2 has an established loss-of-function disease mechanism in the gene-level framework.
- The variant-specific PVS1 assessment states that c.3054G>C is outside the default generic PVS1 null-variant categories.
Sources
PS4 No case-control study or exact-variant enrichment data were identified to show this variant is significantly more common in affected individuals than in controls. The observed population frequency is also well above the PALB2 PM2 threshold, so available evidence does not support PS4. Details ▾Hide ▴
Rule
Case-control studies with p-value ≤0.05 and odds ratio/hazard ratio/relative risk ≥3 or lower 95% CI ≥1.5.
Evidence considered
- PS4 in PALB2 requires case-control evidence.
- The variant is present in gnomAD v4.1 at 214/1614106 alleles.
Still missing
- No exact-variant case-control counts were identified.
Sources
PM2 This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), which is above the PALB2 PM2_Supporting threshold of ≤0.000333%. Available population data therefore do not support PM2. Details ▾Hide ▴
Rule
PM2_Supporting if frequency ≤ 1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- gnomAD v4.1 total AF is 0.000132581.
- PALB2 PM2 applies only when frequency is ≤ 1/300
- 000.
Sources
PP3 SpliceAI predicts no significant splice effect for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of ≥0.2. REVEL is 0.118 and BayesDel is -0.42024, but the PALB2 specification does not support missense PP3 use outside its stated splice rule, so available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Splicing PP3 applies for predicted splice impact with SpliceAI ≥0.2; missense PP3 is otherwise not used in PALB2.
Evidence considered
- SpliceAI max delta score is 0.01.
- REVEL score is 0.118.
- BayesDel score is -0.42024.
Sources
Not assessed · 6 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change has the same established pathogenic amino acid or splicing consequence as a previously classified pathogenic PALB2 variant under the PALB2 PS1 splicing framework. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table.
Evidence considered
- PALB2 uses a PS1 splicing table for application of PS1.
Still missing
- No PALB2 PS1 splicing-table match was identified from the available evidence.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia cases, so PM3 could not be applied. Details ▾Hide ▴
Rule
PM3 point-based Fanconi anemia framework.
Evidence considered
- PALB2 PM3 requires point-based evidence from Fanconi anemia probands.
Still missing
- No phase-confirmed Fanconi anemia proband data were identified.
Sources
PP1 No segregation data were identified for this variant, so the available evidence does not support PP1 at any strength. Details ▾Hide ▴
Rule
LOD/Bayes factor or affected-relative thresholds specified by the PALB2 framework.
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence.
Still missing
- No family-based segregation study or LOD/Bayes factor was identified.
Sources
BS1 The observed gnomAD v4.1 population frequency exceeds the stricter BA1 threshold, so BS1 was not separately counted. Details ▾Hide ▴
Rule
BS1 threshold is lower than BA1 for PALB2.
Evidence considered
- gnomAD v4.1 East Asian AF is 0.00416704
- above both BS1 and BA1 thresholds.
Sources
BS2 No point-based evidence from unaffected individuals or qualifying Fanconi anemia context was identified, so BS2 could not be applied. Details ▾Hide ▴
Rule
BS2 point-based Fanconi anemia framework.
Evidence considered
- PALB2 BS2 requires point-based evidence.
Still missing
- No BS2 point-based case data were identified.
Sources
BS4 No non-segregation data or quantitative evidence showing lack of segregation in affected relatives were identified, so BS4 could not be applied. Details ▾Hide ▴
Rule
LOD/Bayes factor thresholds specified by the PALB2 framework.
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence.
Still missing
- No family non-segregation study or LOD/Bayes factor was identified.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThe PALB2 specification does not use PS2 for this framework. Details ▾Hide ▴
PS3 N/AThe PALB2 specification does not use PS3 in this framework, and no variant-specific validated functional assay evidence was identified for separate application. Details ▾Hide ▴
PM1 N/APM1 is not applicable in the PALB2 specification, and no hotspot evidence supports use of a mutational hotspot rule for this variant. Details ▾Hide ▴
Evidence considered
- PM1 is marked not applicable in the PALB2 specification.
- Cancer Hotspots did not identify a statistically significant hotspot at this residue.
Sources
PM4 N/APM4 is not applicable because this variant is not a PALB2 stop-loss variant and the PALB2 specification does not use PM4 for this type of change. Details ▾Hide ▴
PM5 N/AThe PALB2 specification restricts PM5 to frameshifting, truncating, or qualifying splice loss-of-function variants upstream of p.Tyr1183. This missense variant does not meet that rule. Details ▾Hide ▴
Rule
Apply to qualifying truncating or splice loss-of-function variants upstream of p.Tyr1183.
Evidence considered
- PALB2 PM5 is limited to specified truncating or splice loss-of-function contexts.
Sources
PM6 N/AThe PALB2 specification does not use PM6 for this framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the PALB2 specification. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the PALB2 specification. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PALB2 specification. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the PALB2 specification, and no qualifying benign functional assay evidence was identified for separate use. Details ▾Hide ▴
BP2 N/ABP2 is not applicable in the PALB2 specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the PALB2 specification. Details ▾Hide ▴
BP4 N/AAlthough SpliceAI predicts no significant splice effect (max delta score 0.01), the PALB2 specification does not apply BP4 to missense variants in this context. BP4 was therefore not applied. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.01.
- PALB2 BP4 is not used for missense variants.
Sources
BP5 N/ABP5 is not applicable in the PALB2 specification. Details ▾Hide ▴
BP7 N/ABP7 is used for synonymous or qualifying deep intronic variants, and this variant is a missense substitution. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous and specified deep intronic variants.
Evidence considered
- The variant is p.(Glu1018Asp)
- a missense change.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.3054G>C
- Protein (HGVS p.)
- NP_078951.2:p.(Glu1018Asp)
- GRCh38
- chr16:23621421 C>G
- GRCh37
- chr16:23632742 C>G
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
214 / 1,614,106 alleles
AF 0.000133 · 0 homozygotes · FAF 0.00368
gnomAD v2.1
109 / 282,850 alleles
AF 0.000385 · 0 homozygotes · FAF 0.00444
By genetic ancestry
gnomAD v4.1
AF 0.00013 · 214 / 1,614,106 alleles · 0 hom · FAF 0.0037
| East Asian187 / 44,876 | 0.0042 |
| Remaining individuals19 / 62,510 | 0.0003 |
| South Asian4 / 91,076 | 4.4e-05 |
| Admixed American1 / 60,008 | 1.7e-05 |
| European (non-Finnish)3 / 1,180,004 | 2.5e-06 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00039 · 109 / 282,850 alleles · 0 hom · FAF 0.0044
| East Asian105 / 19,952 | 0.0053 |
| Remaining individuals3 / 7,224 | 0.00042 |
| European (non-Finnish)1 / 129,170 | 7.7e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000132581; MAF= 0.01326%, 214/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00416704; MAF= 0.41670%, 187/44876 alleles, homozygotes = 0); grpmax FAF= 0.00367847.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000385363; MAF= 0.03854%, 109/282850 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00526263; MAF= 0.52626%, 105/19952 alleles, homozygotes = 0); grpmax FAF= 0.00444365.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice effect for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of ≥0.2. REVEL is 0.118 and BayesDel is -0.42024, but the PALB2 specification does not support missense PP3 use outside its stated splice rule, so available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Splicing PP3 applies for predicted splice impact with SpliceAI ≥0.2; missense PP3 is otherwise not used in PALB2.
Evidence considered
- SpliceAI max delta score is 0.01.
- REVEL score is 0.118.
- BayesDel score is -0.42024.
Sources
BP4 N/AAlthough SpliceAI predicts no significant splice effect (max delta score 0.01), the PALB2 specification does not apply BP4 to missense variants in this context. BP4 was therefore not applied. Details ▾Hide ▴
Rule
Splicing BP4 uses SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.01.
- PALB2 BP4 is not used for missense variants.
Sources
BP7 N/ABP7 is used for synonymous or qualifying deep intronic variants, and this variant is a missense substitution. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous and specified deep intronic variants.
Evidence considered
- The variant is p.(Glu1018Asp)
- a missense change.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.118. BayesDel score = -0.42024.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
214 / 1,614,106 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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/126708/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23632742-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23621421-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.3054…
- OncoKB ↗www.oncokb.org/gene/PALB2/E1018D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107875142
- 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= 0.000132581; MAF= 0.01326%, 214/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00416704; MAF= 0.41670%, 187/44876 alleles, homozygotes = 0); grpmax FAF= 0.00367847.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000385363; MAF= 0.03854%, 109/282850 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00526263; MAF= 0.52626%, 105/19952 alleles, homozygotes = 0); grpmax FAF= 0.00444365.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.118. BayesDel score = -0.42024.
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 previously been reported in somatic cancers (COSMIC; COSV55165548, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.