About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1794G>A, p.(Leu598=)
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: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BS1Strong
BS1 · strong
This variant exceeds the PALB2 BS1 threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.04713%, which is above the BS1 threshold of 0.01%, supporting BS1 at strong strength.
BP4Supporting
BP4 · supporting
Computational splicing evidence supports no effect on splicing. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1, so BP4 is met at supporting strength.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.
BP7Supporting
BP7 · supporting
This is a synonymous PALB2 variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is consistent with no significant splice impact, so BP7 is met at supporting strength.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BS1 strong, BP4 supporting, BP6 supporting benign, BP7 supporting; 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
47 / 1,614,132 alleles
gnomAD v4.1: 47 / 1,614,132 alleles. Recorded AF 2.91178e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07454e-05; MAF= 0.00707%, 20/282704 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000801218; MAF= 0.08012%, 20/24962 alleles, homozygotes = 0); grpmax FAF= 0.00056887.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 4 met · 5 not met · 5 not assessed · 14 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.1794G>A (p.Leu598=) variant has been reported in ClinVar with an expert panel Likely Benign classification and additional benign or likely benign clinical laboratory submissions.
In gnomAD v4.1, this variant is present at 47/1614132 alleles (0.00291%) with a grpmax filtering allele frequency of 0.04713%, which is above the PALB2 BS1 threshold of 0.01%; gnomAD v2.1 also shows the variant in population databases, including African/African American individuals.
SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1 and below the PP3 threshold of 0.2.
No criteria match.
Met · 4
BS1 StrongThis variant exceeds the PALB2 BS1 threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.04713%, which is above the BS1 threshold of 0.01%, supporting BS1 at strong strength. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 grpmax FAF is 0.00047131 (0.04713%).
- The highest observed population frequency in gnomAD v4.1 is 46/75050 alleles in African/African American individuals (0.06129%)
- with 0 homozygotes.
- gnomAD v2.1 also shows the variant at 20/282704 alleles overall and 20/24962 alleles in African/African American individuals.
Sources
BP4 SupportingComputational splicing evidence supports no effect on splicing. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1, so BP4 is met at supporting strength. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants
Evidence considered
- SpliceAI scores are DS_AG 0.06
- DS_AL 0.01
- DS_DG 0.00
- and DS_DL 0.00
- maximum delta score 0.06.
- No REVEL or BayesDel score was available for this synonymous substitution.
Sources
BP6 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign. Details ▾Hide ▴
BP7 SupportingThis is a synonymous PALB2 variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is consistent with no significant splice impact, so BP7 is met at supporting strength. Details ▾Hide ▴
Rule
BP7: Use for synonymous and deep intronic variants defined as further than +7 donor and -21 acceptor sites; BP7(RNA): observed lack of aberrant RNA defect for silent substitutions and intronic variants
Evidence considered
- c.1794G>A results in p.(Leu598=)
- a synonymous substitution.
- SpliceAI maximum delta score is 0.06.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This synonymous PALB2 variant does not fall into the default loss-of-function variant classes for PVS1, and available splicing evidence does not support a loss-of-function transcript. SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, so PVS1 is not supported. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 has gene-level PVS1 eligibility in the CSPEC/VCEP framework.
- c.1794G>A is a synonymous substitution
- p.(Leu598=).
- The generic PVS1 scaffold does not place this variant in a default null-variant bucket.
- SpliceAI maximum delta score is 0.06.
Sources
PS1 Available evidence does not identify that this variant produces the same established pathogenic splicing effect as another PALB2 variant. SpliceAI predicts no significant splice impact, so PS1 is not supported on the current evidence. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- SpliceAI maximum delta score is 0.06.
- No same-splicing pathogenic comparator was identified.
Still missing
- No exact PALB2 PS1 splicing-table match was identified in the reviewed materials.
Sources
PM2 This variant is present in gnomAD v4.1 at 47/1614132 alleles (0.00291%), which is above the PALB2 PM2_Supporting threshold of 1/300000 (0.000333%). PM2 is therefore not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 total AF is 2.91178e-05 (0.00291%)
- 47/1614132 alleles
- 0 homozygotes.
- PALB2 PM2_Supporting threshold is ≤0.000333% in gnomAD v4.
Sources
PP3 Computational splicing evidence does not support a damaging effect. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 PP3 threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites
Evidence considered
- SpliceAI scores are DS_AG 0.06
- DS_AL 0.01
- DS_DG 0.00
- and DS_DL 0.00
- maximum delta score 0.06.
- No REVEL or BayesDel score was available for this synonymous substitution.
Sources
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 0.04713%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 grpmax FAF is 0.00047131 (0.04713%).
- PALB2 BA1 threshold is >0.1% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 No case-control study, odds ratio, or quantified enrichment data were identified for this variant, so PS4 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
- No quantified affected-versus-control enrichment data were identified.
Still missing
- No variant-specific case-control data or odds ratio were identified.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic PALB2 variant in a proband meeting the Fanconi anemia scoring framework, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 = 2 points; PM3_Supporting = 1 point; PM3_Strong ≥4 points; PM3_VeryStrong ≥8 points
Evidence considered
- No PM3 point-generating proband data were identified.
Still missing
- No phased biallelic PALB2 case data were identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD condition: Supporting LOD ≥0.3, Moderate LOD ≥0.60, Strong LOD ≥1.26; AR condition: segregation in 1, 2, or ≥3 affected relatives
Evidence considered
- No family-based segregation evidence was identified.
Still missing
- No LOD score
- Bayes factor
- or informative family segregation data were identified.
Sources
BS2 No scored observations in unaffected individuals or other BS2 point-based evidence were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2 = 4 points
Evidence considered
- No BS2 scoring data were identified.
Still missing
- No BS2 point-generating observations were identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
Supporting LOD ≤-0.32 or LR ≤0.48; Moderate LOD ≤-0.64 or LR ≤0.23; Strong LOD ≤-1.28 or LR ≤0.053:1
Evidence considered
- No family-based non-segregation evidence was identified.
Still missing
- No LOD score
- Bayes factor
- or informative non-segregation family data were identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PS3 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PM1 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PM4 N/AThis criterion is not applicable in the PALB2 VCEP specification for this variant type. Details ▾Hide ▴
PM5 N/AThis synonymous variant does not meet the PALB2 PM5 framework, which is reserved for qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183; also qualifying splice variants with NMD-prone RNA evidence
Evidence considered
- c.1794G>A is a synonymous substitution
- p.(Leu598=).
- PALB2 PM5 applies to qualifying truncating or splice variants.
Sources
PM6 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PP2 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PP4 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
PP5 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BS3 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP1 N/AThis PALB2 rule applies only to missense variants. This variant is synonymous, so BP1 is not applicable. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- c.1794G>A results in p.(Leu598=)
- a synonymous substitution.
- PALB2 BP1 applies to all missense variants.
Sources
BP2 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP3 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
BP5 N/AThis criterion is not applicable in the PALB2 VCEP specification. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.1794G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Leu598=)
- GRCh38
- chr16:23630360 C>T
- GRCh37
- chr16:23641681 C>T
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
47 / 1,614,132 alleles
AF 2.91e-05 · 0 homozygotes · FAF 0.000471
gnomAD v2.1
20 / 282,704 alleles
AF 7.07e-05 · 0 homozygotes · FAF 0.000569
By genetic ancestry
gnomAD v4.1
AF 2.9e-05 · 47 / 1,614,132 alleles · 0 hom · FAF 0.00047
| African/African American46 / 75,050 | 0.00061 |
| Remaining individuals1 / 62,504 | 1.6e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 7.1e-05 · 20 / 282,704 alleles · 0 hom · FAF 0.00057
| African/African American20 / 24,962 | 0.0008 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.91178e-05; MAF= 0.00291%, 47/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000612925; MAF= 0.06129%, 46/75050 alleles, homozygotes = 0); grpmax FAF= 0.00047131.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07454e-05; MAF= 0.00707%, 20/282704 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000801218; MAF= 0.08012%, 20/24962 alleles, homozygotes = 0); grpmax FAF= 0.00056887.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational splicing evidence supports no effect on splicing. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1, so BP4 is met at supporting strength. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants
Evidence considered
- SpliceAI scores are DS_AG 0.06
- DS_AL 0.01
- DS_DG 0.00
- and DS_DL 0.00
- maximum delta score 0.06.
- No REVEL or BayesDel score was available for this synonymous substitution.
Sources
BP7 SupportingThis is a synonymous PALB2 variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is consistent with no significant splice impact, so BP7 is met at supporting strength. Details ▾Hide ▴
Rule
BP7: Use for synonymous and deep intronic variants defined as further than +7 donor and -21 acceptor sites; BP7(RNA): observed lack of aberrant RNA defect for silent substitutions and intronic variants
Evidence considered
- c.1794G>A results in p.(Leu598=)
- a synonymous substitution.
- SpliceAI maximum delta score is 0.06.
Sources
PP3 Computational splicing evidence does not support a damaging effect. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 PP3 threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
Splicing: Predicted impact via splicing (SpliceAI ≥0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites
Evidence considered
- SpliceAI scores are DS_AG 0.06
- DS_AL 0.01
- DS_DG 0.00
- and DS_DL 0.00
- maximum delta score 0.06.
- No REVEL or BayesDel score was available for this synonymous substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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
47 / 1,614,132 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/219588/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641681-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23630360-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.1794…
- OncoKB ↗www.oncokb.org/gene/PALB2/L598=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1794G%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= 2.91178e-05; MAF= 0.00291%, 47/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000612925; MAF= 0.06129%, 46/75050 alleles, homozygotes = 0); grpmax FAF= 0.00047131.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07454e-05; MAF= 0.00707%, 20/282704 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000801218; MAF= 0.08012%, 20/24962 alleles, homozygotes = 0); grpmax FAF= 0.00056887.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely 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 = 0.06).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.