About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.3249G>C, p.(Glu1083Asp)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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
BS1Strong
BS1 · strong
Population frequency supports a benign interpretation. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is above the PALB2 BS1 threshold of >0.01%.
BP1Supporting
BP1 · supporting
This is a missense variant, NM_024675.3:c.3249G>C (p.Glu1083Asp, p.E1083D). Under the PALB2 VCEP specification, BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP1 supporting, BP6 supporting benign; maps to Likely 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
86 / 1,613,962 alleles
gnomAD v4.1: 86 / 1,613,962 alleles. Recorded AF 5.3285e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00021919; MAF= 0.02192%, 62/282860 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00163657; MAF= 0.16366%, 58/35440 alleles, homozygotes = 0); grpmax FAF= 0.0013313.
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 · 3 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 c.3249G>C (p.Glu1083Asp, p.E1083D) variant has been reported in ClinVar and is classified there as benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
In gnomAD v4, the variant has a total allele frequency of 0.00533% and a grpmax filtering allele frequency of 0.088684%, which is above the PALB2 BS1 threshold of 0.01% but below the BA1 threshold of 0.1%.
Computational data predict no significant splice effect, with a SpliceAI max delta score of 0.00; REVEL is 0.081 and BayesDel is -0.49371, although PALB2 VCEP guidance does not apply missense PP3 or BP4 for this gene.
No criteria match.
Met · 3
BS1 StrongPopulation frequency supports a benign interpretation. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is above the PALB2 BS1 threshold of >0.01%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 grpmax FAF 0.00088684
- PALB2 BS1 threshold >0.01% in gnomAD v4
Sources
BP1 SupportingThis is a missense variant, NM_024675.3:c.3249G>C (p.Glu1083Asp, p.E1083D). Under the PALB2 VCEP specification, BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- Variant consequence p.Glu1083Asp / p.E1083D
- PALB2 BP1 applies to all missense variants
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 PVS1 was not applied. This variant is a missense substitution rather than a canonical null variant, it is not at a canonical ±1/2 splice site, and SpliceAI predicts no significant splice impact (max delta score 0.00). No RNA evidence showing an observed splice defect was identified. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 is eligible for PVS1 in principle
- Variant-level PVS1 scaffold places this variant outside default null buckets
- SpliceAI max delta score 0.00
- Variant is not canonical splice consensus
Still missing
- No RNA study demonstrating a splice defect was identified.
- No PALB2 PVS1 decision-tree evidence supporting a loss-of-function mechanism for this exact variant was identified.
Sources
PM2 Population frequency does not meet the PALB2 PM2_Supporting threshold. In gnomAD v4, the total allele frequency is 0.00533%, which is above the PM2_Supporting threshold of ≤0.000333%. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4 total AF 0.000053285
- PALB2 PM2_Supporting threshold ≤0.00000333
Sources
BA1 Population frequency does not meet the PALB2 BA1 threshold. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is below the BA1 threshold of >0.1%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 grpmax FAF 0.00088684
- PALB2 BA1 threshold >0.1% in gnomAD v4
Sources
Not assessed · 5 · no assessment recorded
PS4 No qualifying case-control evidence was identified for this variant. No odds ratio, relative risk, hazard ratio, or lower 95% confidence interval meeting the PALB2 PS4 threshold was available, so PS4 was not assessed. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 AND (odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- ClinVar reports the variant but does not provide a qualifying PALB2 PS4 case-control statistic
- PALB2 PS4 requires case-control evidence
Still missing
- No qualifying case-control statistic was identified.
- No PALB2 PS4-eligible enrichment study 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 Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3_VeryStrong ≥ 8 points; PM3_Strong ≥ 4 points; PM3 = 2 points; PM3_Supporting = 1 point
Evidence considered
- PALB2 PM3 requires Fanconi anemia trans observations with point assignment
Still missing
- No informative trans observations were identified.
- No PM3 point assignment could be made.
Sources
PP1 No segregation data were identified for this variant, and no LOD score or Bayes factor was available, so PP1 was not assessed. Details ▾Hide ▴
Rule
AD: LOD ≥1.26 / ≥0.60 / ≥0.3 or Bayes Factor ≥18:1 / ≥4:1 / ≥2:1; AR: segregation in ≥3 / 2 / 1 affected relatives
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence
Still missing
- No co-segregation study was identified.
- No quantitative segregation score was available.
Sources
BS2 No data were identified showing this variant in informative unaffected individuals under the PALB2 BS2 point-based framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 ≥ 4 points; BS2_Moderate = 2 points; BS2_Supporting = 1 point
Evidence considered
- PALB2 BS2 requires informative unaffected individuals and point assignment
Still missing
- No informative unaffected-carrier observations were identified.
- No BS2 point assignment could be made.
Sources
BS4 No family study showing lack of segregation was identified, and no LOD score or Bayes factor was available for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1; lower strengths at LOD ≤ -.64 and ≤ -.32
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence
Still missing
- No non-segregation study was identified.
- No LOD score or Bayes factor was available.
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable here because the PALB2 VCEP does not use PS1 for missense changes, and no evidence was identified that this variant causes the same splice effect as an established pathogenic variant. Details ▾Hide ▴
Evidence considered
- Variant is missense
- SpliceAI max delta score 0.00
- PALB2 PS1 missense: do not use
Still missing
- No qualifying PALB2 PS1 splicing-table match was identified.
Sources
PS2 N/APS2 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
PS3 N/APS3 is not applicable under the PALB2 VCEP framework for this variant. The PALB2 specification directs relevant RNA evidence into PVS1-related or BP7-related assessment rather than PS3. Details ▾Hide ▴
PM1 N/APM1 is not applicable under the PALB2 VCEP framework because missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this variant is not a stop-loss variant. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- PALB2 PM4 is reserved for stop-loss variants
Sources
PM5 N/APM5 is not applicable because the PALB2 VCEP does not use PM5 for missense changes. This criterion is reserved for qualifying truncating or splice variants under the PALB2 specification. Details ▾Hide ▴
PM6 N/APM6 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
PP3 N/AAlthough SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the PP3 splice threshold of ≥0.2), the PALB2 VCEP does not apply PP3 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense PP3 adjudication. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: Predicted impact via splicing (SpliceAI ≥0.2).
Evidence considered
- SpliceAI max delta score 0.00
- REVEL 0.081
- BayesDel -0.49371
- PALB2 PP3 missense: do not use
Sources
PP4 N/APP4 is not applicable under the PALB2 VCEP framework for autosomal dominant PALB2-related cancer predisposition. Details ▾Hide ▴
PP5 N/APP5 is not for use under the PALB2 VCEP framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable under the PALB2 VCEP framework for this variant. The PALB2 specification directs RNA evidence into BP7-variable or PVS1-related assessment rather than BS3. Details ▾Hide ▴
BP2 N/ABP2 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable under the PALB2 VCEP framework because PALB2 is not considered to have a relevant repetitive region for this criterion. Details ▾Hide ▴
BP4 N/AAlthough SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of ≤0.1), the PALB2 VCEP does not apply BP4 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense BP4 adjudication. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL 0.081
- BayesDel -0.49371
- PALB2 BP4 missense: do not use
Sources
BP5 N/ABP5 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence p.Glu1083Asp / p.E1083D
- PALB2 BP7 applies to synonymous and deep intronic variants
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.3249G>C
- Protein (HGVS p.)
- NP_078951.2:p.(Glu1083Asp)
- GRCh38
- chr16:23607965 C>G
- GRCh37
- chr16:23619286 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
—
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
86 / 1,613,962 alleles
AF 5.33e-05 · 0 homozygotes · FAF 0.000887
gnomAD v2.1
62 / 282,860 alleles
AF 0.000219 · 0 homozygotes · FAF 0.00133
By genetic ancestry
gnomAD v4.1
AF 5.3e-05 · 86 / 1,613,962 alleles · 0 hom · FAF 0.00089
| Admixed American66 / 59,994 | 0.0011 |
| European (non-Finnish)20 / 1,179,992 | 1.7e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00022 · 62 / 282,860 alleles · 0 hom · FAF 0.0013
| Admixed American58 / 35,440 | 0.0016 |
| European (non-Finnish)4 / 129,180 | 3.1e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.3285e-05; MAF= 0.00533%, 86/1613962 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00110011; MAF= 0.11001%, 66/59994 alleles, homozygotes = 0); grpmax FAF= 0.00088684.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00021919; MAF= 0.02192%, 62/282860 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00163657; MAF= 0.16366%, 58/35440 alleles, homozygotes = 0); grpmax FAF= 0.0013313.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AAlthough SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the PP3 splice threshold of ≥0.2), the PALB2 VCEP does not apply PP3 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense PP3 adjudication. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: Predicted impact via splicing (SpliceAI ≥0.2).
Evidence considered
- SpliceAI max delta score 0.00
- REVEL 0.081
- BayesDel -0.49371
- PALB2 PP3 missense: do not use
Sources
BP4 N/AAlthough SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of ≤0.1), the PALB2 VCEP does not apply BP4 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense BP4 adjudication. Details ▾Hide ▴
Rule
Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL 0.081
- BayesDel -0.49371
- PALB2 BP4 missense: do not use
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence p.Glu1083Asp / p.E1083D
- PALB2 BP7 applies to 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 = 0.081. BayesDel score = -0.49371.
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
86 / 1,613,962 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/126726/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23619286-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23607965-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.3249…
- OncoKB ↗www.oncokb.org/gene/PALB2/E1083D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107878246
- 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= 5.3285e-05; MAF= 0.00533%, 86/1613962 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00110011; MAF= 0.11001%, 66/59994 alleles, homozygotes = 0); grpmax FAF= 0.00088684.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00021919; MAF= 0.02192%, 62/282860 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00163657; MAF= 0.16366%, 58/35440 alleles, homozygotes = 0); grpmax FAF= 0.0013313.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (2 clinical laboratories) and as likely benign (1 clinical laboratory) 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 = 0.00). REVEL score = 0.081. BayesDel score = -0.49371.
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; COSV55168291, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.