About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.109C>A, p.(Arg37Ser)
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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
This variant is present in gnomAD v4.1 with a highest observed subpopulation frequency of 0.01603% in the African/African American population, which is above the PALB2 BS1 threshold of 0.01%. This supports BS1 at strong strength.
BP1Supporting
BP1 · supporting
This is a missense variant, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense changes are thought to be exceedingly rare in PALB2 relative to truncating disease-causing variants. This supports BP1 at supporting strength.
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; 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
16 / 1,612,736 alleles
gnomAD v4.1: 16 / 1,612,736 alleles. Recorded AF 9.92103e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123047; MAF= 0.01230%, 2/16254 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
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.
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
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: 2 met · 5 not met · 5 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.109C>A (p.Arg37Ser; p.R37S) variant has been reported in ClinVar with an expert-panel classification of uncertain significance, alongside additional clinical laboratory submissions of uncertain significance and likely benign.
This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), with a highest observed African/African American subpopulation frequency of 0.01603%, which is above the PALB2 BS1 threshold of 0.01% and below the BA1 threshold of 0.1%.
SpliceAI predicts no meaningful splice effect for this variant (max delta score 0.00), which does not meet the PALB2 PP3 splicing threshold of 0.2 and does not support RNA-based PVS1 application.
REVEL (0.195) and BayesDel (0.120598) were noted, but the PALB2 VCEP does not use missense protein predictors for PP3 or BP4, while BP1 is applied to PALB2 missense variants under this framework.
No criteria match.
Met · 2
BS1 StrongThis variant is present in gnomAD v4.1 with a highest observed subpopulation frequency of 0.01603% in the African/African American population, which is above the PALB2 BS1 threshold of 0.01%. This supports BS1 at strong strength. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 highest subpopulation AF was 0.000160291 (12/74
- 864 alleles
- 0.01603%).
- PALB2 BS1 requires grpmax filtering AF >0.01% in gnomAD v4.
Sources
BP1 SupportingThis is a missense variant, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense changes are thought to be exceedingly rare in PALB2 relative to truncating disease-causing variants. This supports BP1 at supporting strength. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- The variant is a missense substitution
- p.Arg37Ser.
- PALB2 VCEP applies BP1 to all missense variants.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This missense variant does not fall into a PALB2 loss-of-function variant class for default PVS1 use, and no RNA evidence or splice prediction supports a loss-of-function transcript effect. SpliceAI showed a max delta score of 0.00, so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- PALB2 is PVS1-eligible at the gene level in the VCEP framework.
- The variant is a missense substitution rather than a nonsense
- frameshift
- or canonical ±1
- 2 splice variant.
- SpliceAI max delta score was 0.00.
Sources
PS1 Available evidence does not show that this variant matches a PALB2 pathogenic splicing-equivalence entry, and the PALB2 VCEP does not use PS1 for missense changes. Therefore PS1 is not met. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table
Evidence considered
- PALB2 PS1 is directed to the PALB2 splicing table rather than protein-equivalent missense changes.
- SpliceAI did not predict a splice effect.
Sources
PM2 This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), which is above the PALB2 PM2_Supporting threshold of 0.000333%. Therefore PM2 is not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 total AF was 9.92103e-06 (0.00099%).
- PALB2 PM2 requires frequency ≤1/300
- 000 (0.000333%) in gnomAD v4.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL was 0.195 and BayesDel was 0.120598, but the PALB2 VCEP does not use missense protein predictors for PP3. Therefore 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 max delta score was 0.00.
- REVEL score was 0.195.
- BayesDel score was 0.120598.
- PALB2 PP3 is restricted to qualifying splicing predictions rather than missense protein prediction.
Sources
BA1 The highest observed gnomAD v4.1 subpopulation frequency is 0.01603% in the African/African American population, which is below the PALB2 BA1 threshold of 0.1%. Therefore BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 highest subpopulation AF was 0.000160291 (0.01603%).
- PALB2 BA1 requires grpmax filtering AF >0.1% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control study was identified showing a significant increase in affected individuals that meets the PALB2 PS4 threshold of p≤0.05 with OR, HR, or RR ≥3 or lower 95% CI ≥1.5. Therefore PS4 remains unassessed. 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
- ClinVar reports the variant but does not provide a qualifying PS4 case-control result.
- No case-control metric meeting the PALB2 PS4 rule was identified.
Still missing
- No qualifying PALB2-specific case-control study for this exact variant was identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 remains unassessed. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so there is no basis to calculate the PALB2 PP1 LOD or Bayes factor thresholds. PP1 remains unassessed. Details ▾Hide ▴
Rule
AD: LOD ≥0.3, ≥0.60, or ≥1.26 / Bayes Factor ≥2:1, ≥4:1, or ≥18:1; AR: segregation in 1, 2, or ≥3 affected relatives
Evidence considered
- No affected-family segregation evidence was identified.
Still missing
- No family segregation data or quantitative segregation analysis were identified.
Sources
BS2 No evidence was identified showing this variant in healthy adults under the PALB2 Fanconi anemia BS2 point-based framework. Therefore BS2 remains unassessed. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2 ≥4 points
Evidence considered
- No BS2 point-based evidence was identified.
Still missing
- No qualifying unaffected-carrier or BS2 point-scoring data were identified.
Sources
BS4 No non-segregation data were identified for this variant, so the PALB2 BS4 LOD or Bayes factor thresholds cannot be evaluated. BS4 remains unassessed. Details ▾Hide ▴
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThe PALB2 VCEP does not use PS2 for this disease setting, and no informative confirmed de novo evidence is available for this variant. Details ▾Hide ▴
PS3 N/AThe PALB2 VCEP does not use PS3 for this setting, and no reviewed variant-specific functional evidence was identified that would override that framework here. Details ▾Hide ▴
PM1 N/APM1 is not used by the PALB2 VCEP because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. Cancer Hotspots also did not identify a significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP marks PM1 as not applicable.
- Cancer Hotspots did not show a statistically significant hotspot.
Sources
PM4 N/AThis variant is a missense substitution, not a stop-loss variant, and PM4 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
PM5 N/AThe PALB2 VCEP does not use PM5 for missense changes. This variant is a missense substitution without evidence for a truncating or qualifying splice-loss mechanism, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- PALB2 PM5 is reserved for truncating or qualifying splice variants
- not missense changes.
- SpliceAI did not predict a splice effect.
Sources
PM6 N/AThe PALB2 VCEP does not use PM6 for this disease setting, and no assumed de novo evidence was identified for this variant. Details ▾Hide ▴
PP2 N/AThe PALB2 VCEP does not use PP2 because missense variation is not an established disease mechanism for PALB2. Details ▾Hide ▴
PP4 N/APP4 is not applicable under the PALB2 VCEP framework for the autosomal dominant cancer-predisposition setting because the phenotype is not sufficiently specific to PALB2 alone. Details ▾Hide ▴
PP5 N/APP5 is not used by this VCEP, so external assertions alone are not applied as evidence here. Details ▾Hide ▴
BS3 N/AThe PALB2 VCEP does not use BS3 for this setting. No reviewed RNA study supporting an alternative RNA-based benign code was identified for this exact variant. Details ▾Hide ▴
BP2 N/ABP2 is not applicable under the PALB2 VCEP framework for this setting. Details ▾Hide ▴
BP3 N/AThis variant is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
BP4 N/AAlthough SpliceAI predicts no splice effect with a max delta score of 0.00, the PALB2 VCEP does not apply BP4 to missense variants. Therefore BP4 is not applicable for this missense change. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score was 0.00.
- PALB2 BP4 states not to apply BP4 for missense variants.
Sources
BP5 N/ABP5 is not applicable under the PALB2 VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used by this VCEP, so outside benign assertions are not applied as independent evidence here. Details ▾Hide ▴
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- PALB2 BP7 is directed to synonymous and deep intronic variants or RNA evidence for those variant types.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.109C>A
- Protein (HGVS p.)
- NP_078951.2:p.(Arg37Ser)
- GRCh38
- chr16:23637952 G>T
- GRCh37
- chr16:23649273 G>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
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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
16 / 1,612,736 alleles
AF 9.92e-06 · 0 homozygotes · FAF 9.22e-05
gnomAD v2.1
4 / 251,456 alleles
AF 1.59e-05 · 0 homozygotes · FAF 2.13e-05
By genetic ancestry
gnomAD v4.1
AF 9.9e-06 · 16 / 1,612,736 alleles · 0 hom · FAF 9.2e-05
| African/African American12 / 74,864 | 0.00016 |
| Admixed American2 / 59,984 | 3.3e-05 |
| Remaining individuals2 / 62,440 | 3.2e-05 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 1.6e-05 · 4 / 251,456 alleles · 0 hom · FAF 2.1e-05
| African/African American2 / 16,254 | 0.00012 |
| Admixed American1 / 34,588 | 2.9e-05 |
| European (non-Finnish)1 / 113,750 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.92103e-06; MAF= 0.00099%, 16/1612736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160291; MAF= 0.01603%, 12/74864 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123047; MAF= 0.01230%, 2/16254 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL was 0.195 and BayesDel was 0.120598, but the PALB2 VCEP does not use missense protein predictors for PP3. Therefore 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 max delta score was 0.00.
- REVEL score was 0.195.
- BayesDel score was 0.120598.
- PALB2 PP3 is restricted to qualifying splicing predictions rather than missense protein prediction.
Sources
BP4 N/AAlthough SpliceAI predicts no splice effect with a max delta score of 0.00, the PALB2 VCEP does not apply BP4 to missense variants. Therefore BP4 is not applicable for this missense change. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score was 0.00.
- PALB2 BP4 states not to apply BP4 for missense variants.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- PALB2 BP7 is directed to synonymous and deep intronic variants or RNA evidence for those variant types.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.195. BayesDel score = 0.120598.
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
16 / 1,612,736 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/185108/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649273-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23637952-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.109C…
- OncoKB ↗www.oncokb.org/gene/PALB2/R37S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.109C%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= 9.92103e-06; MAF= 0.00099%, 16/1612736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160291; MAF= 0.01603%, 12/74864 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123047; MAF= 0.01230%, 2/16254 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (12 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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.195. BayesDel score = 0.120598.
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.