About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.104T>C, p.(Leu35Pro)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 6.196170766466323e-07 (0.0000619617%; 1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300000). This supports PM2 at supporting strength.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense substitution, p.(Leu35Pro), and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism in PALB2.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
1 / 1,613,900 alleles
gnomAD v4.1: 1 / 1,613,900 alleles. Recorded AF 6.19617e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 · 7 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.104T>C (p.Leu35Pro) variant has not been observed in COSMIC and has been reported in ClinVar with an overall expert-panel classification of uncertain significance, alongside individual clinical laboratory submissions of likely pathogenic and uncertain significance.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.0000619617% (1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.
In published functional studies, p.(Leu35Pro) disrupted the BRCA1-PALB2 interaction, impaired homologous recombination and homology-directed repair, reduced RAD51 foci formation, and increased sensitivity to cisplatin and PARP inhibition, findings consistent with a damaging effect on PALB2 function.
In silico splice prediction does not support an RNA effect, with SpliceAI showing a maximum delta score of 0.01; REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification does not use missense predictor data for PP3 or BP4.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 6.196170766466323e-07 (0.0000619617%; 1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300000). This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting: frequency <=1/300000 (0.000333%) in gnomAD v4
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 AF 6.196170766466323e-07
- PALB2 PM2 threshold <=0.000333%
Sources
BP1 SupportingThis variant is a missense substitution, p.(Leu35Pro), and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism in PALB2. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Leu35Pro), and does not fall into the PALB2 or generic PVS1 null-variant categories. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, so available evidence does not support a predicted or observed loss-of-function mechanism for this variant. Details ▾Hide ▴
Rule
PALB2 PVS1 decision tree; missense variant without splice/null evidence does not meet PVS1
Evidence considered
- PALB2 VCEP PVS1 framework
- generic PVS1 scaffold classifies this variant outside default null buckets
- SpliceAI max delta score 0.01
Still missing
- No RNA study was identified showing abnormal splicing or a null transcript for this variant.
Sources
PS1 This variant is a missense change, and the PALB2 specification states PS1 should not be used for missense variants. No splice-table evidence was identified showing that this nucleotide change has the same established splice effect as a previously classified pathogenic variant. Details ▾Hide ▴
Rule
PALB2 PS1 applies to splicing evidence only; do not use for missense changes
Evidence considered
- PALB2 VCEP excludes PS1 for missense changes
- SpliceAI max delta score 0.01
Still missing
- No PALB2 PS1 splicing-table match was identified for this variant.
Sources
PM5 This variant is a missense change, and the PALB2 specification states PM5 should not be used for missense variants. No qualifying truncating or splice-related scenario for PALB2 PM5_Supporting was identified. Details ▾Hide ▴
Rule
PALB2 PM5_Supporting applies to qualifying truncating or splice variants, not missense changes
Evidence considered
- PALB2 VCEP PM5 excludes missense changes
Sources
PP3 REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification states PP3 should not be used for missense predictor data. For splicing, SpliceAI shows a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2, so computational evidence does not support PP3. Details ▾Hide ▴
Rule
PP3 only for splicing with SpliceAI >=0.2; do not use for missense predictors
Evidence considered
- REVEL 0.35
- BayesDel 0.236696
- SpliceAI max delta score 0.01
- PALB2 PP3 missense exclusion
Sources
BA1 The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles in the non-Finnish European population), which is far below the PALB2 BA1 threshold of greater than 0.1%. This does not support BA1. Details ▾Hide ▴
Rule
BA1 requires grpmax filtering AF >0.1% in gnomAD v4
Evidence considered
- gnomAD v4.1 highest population AF 8.476300264460568e-07
- PALB2 BA1 threshold >0.1%
Sources
BS1 The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles), which is below the PALB2 BS1 threshold of greater than 0.01%. This does not support BS1. Details ▾Hide ▴
Rule
BS1 requires grpmax filtering AF >0.01% in gnomAD v4
Evidence considered
- gnomAD v4.1 highest population AF 8.476300264460568e-07
- PALB2 BS1 threshold >0.01%
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splice threshold of 0.1. However, the PALB2 specification states BP4 should not be applied for missense variants, so this does not support BP4 for p.(Leu35Pro). Details ▾Hide ▴
Rule
BP4 splice rule <=0.1 exists, but do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 missense exclusion
Sources
Not assessed · 5 · no assessment recorded
PS4 This variant has been reported in ClinVar and one publication described segregation in a family with breast cancer, but no case-control study with p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk greater than or equal to 3 was identified. Available evidence is insufficient to determine whether affected-case prevalence is significantly increased over controls. Details ▾Hide ▴
Rule
Case-control studies with p<=0.05 and OR/HR/RR >=3 or lower 95% CI >=1.5
Evidence considered
- ClinVar reports variant submissions
- family report in PMID:28319063
- no qualifying case-control statistics identified
Still missing
- No variant-specific case-control dataset or odds ratio meeting the PALB2 PS4 threshold was identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be evaluated from the available data. Details ▾Hide ▴
Rule
PM3 point-based Fanconi anemia framework
Evidence considered
- No in-trans FA evidence identified
Still missing
- No phased biallelic Fanconi anemia observations were identified for this variant.
Sources
PP1 One publication states that this variant segregated in a family with a strong history of breast cancer, but no quantitative segregation data such as LOD score or Bayes factor were identified. This is not enough to assign PP1 under the PALB2 specification. Details ▾Hide ▴
Rule
PP1 requires quantitative segregation thresholds
Evidence considered
- family segregation mentioned in PMID:28319063
- PALB2 requires quantitative segregation analysis
Still missing
- No LOD score
- Bayes factor
- or count of informative meioses was identified for this variant.
Sources
BS2 No evidence was identified showing this variant in healthy individuals meeting the PALB2 BS2 point-based framework, so BS2 cannot be assessed from the available data. Details ▾Hide ▴
Rule
BS2 point-based Fanconi anemia framework
Evidence considered
- No BS2-qualifying healthy adult observations identified
Still missing
- No qualifying unaffected-carrier data meeting PALB2 BS2 point thresholds were identified.
Sources
BS4 No quantitative evidence of lack of segregation such as a negative LOD score or Bayes factor was identified for this variant, so BS4 cannot be assessed from the available data. Details ▾Hide ▴
Rule
BS4 requires quantitative non-segregation thresholds
Evidence considered
- No BS4-qualifying family non-segregation data identified
Still missing
- No non-segregation analysis meeting PALB2 BS4 thresholds was identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not applicable in the PALB2 specification because informative de novo observations are not used for PALB2-related disease assessment. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PS2 applicability statement
Sources
PS3 N/APublished functional studies report damaging effects for p.(Leu35Pro), including loss of BRCA1-PALB2 interaction, homologous recombination defects, reduced RAD51 foci, and increased sensitivity to cisplatin and PARP inhibition. However, the PALB2 specification marks PS3 as not applicable, so these data are not coded as PS3 in this framework. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- BRCA1-PALB2 interaction assay abnormal
- HDR/HR assays abnormal
- drug sensitivity and RAD51 foci assays abnormal
Sources
PM1 N/AThis criterion is not applicable for PALB2 because missense pathogenic variation in PALB2 is not treated as an established mechanism for PM1-based hotspot or domain interpretation in this specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PM1 applicability statement
Sources
PM4 N/AThis criterion is not applicable because the variant is not a stop-loss change, and the PALB2 specification does not use PM4 for in-frame changes less than a single exon. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PM4 applicability statement
Sources
PM6 N/AThis criterion is not applicable in the PALB2 specification because de novo observations are not used for PALB2-related disease assessment. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PM6 applicability statement
Sources
PP2 N/AThis criterion is not applicable because the PALB2 specification does not use PP2 for missense variants. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PP2 applicability statement
Sources
PP4 N/AThis criterion is not applicable because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for PP4 in the autosomal dominant setting under this specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PP4 applicability statement
Sources
PP5 N/AThis criterion is not used by the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP PP5 applicability statement
Sources
BS3 N/AAlthough published studies report abnormal rather than normal function for p.(Leu35Pro), the PALB2 specification marks BS3 as not applicable. Functional evidence is therefore not coded as BS3 in this framework. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- published assays show damaging rather than normal function
- PALB2 VCEP BS3 not applicable
Sources
BP2 N/AThis criterion is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP BP2 applicability statement
Sources
BP3 N/AThis criterion is not applicable because the variant is not an in-frame insertion or deletion in a repetitive region, and the PALB2 specification does not use BP3 for PALB2. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP BP3 applicability statement
Sources
BP5 N/AThis criterion is not applicable in the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP BP5 applicability statement
Sources
BP6 N/AThis criterion is not used by the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable per PALB2 VCEP
Evidence considered
- PALB2 VCEP BP6 applicability statement
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so the PALB2 BP7 framework is not applicable. Details ▾Hide ▴
Rule
Not applicable for this missense variant under PALB2 VCEP
Evidence considered
- variant is missense
- PALB2 BP7 scope limited to synonymous/deep intronic or RNA evidence for those classes
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.104T>C
- Protein (HGVS p.)
- NP_078951.2:p.(Leu35Pro)
- GRCh38
- chr16:23638074 A>G
- GRCh37
- chr16:23649395 A>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
1 / 1,613,900 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,900 alleles · 0 hom
| European (non-Finnish)1 / 1,179,760 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19617e-07; MAF= 0.00006%, 1/1613900 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4763e-07; MAF= 0.00008%, 1/1179760 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification states PP3 should not be used for missense predictor data. For splicing, SpliceAI shows a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2, so computational evidence does not support PP3. Details ▾Hide ▴
Rule
PP3 only for splicing with SpliceAI >=0.2; do not use for missense predictors
Evidence considered
- REVEL 0.35
- BayesDel 0.236696
- SpliceAI max delta score 0.01
- PALB2 PP3 missense exclusion
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splice threshold of 0.1. However, the PALB2 specification states BP4 should not be applied for missense variants, so this does not support BP4 for p.(Leu35Pro). Details ▾Hide ▴
Rule
BP4 splice rule <=0.1 exists, but do not apply for missense variants
Evidence considered
- SpliceAI max delta score 0.01
- PALB2 BP4 missense exclusion
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so the PALB2 BP7 framework is not applicable. Details ▾Hide ▴
Rule
Not applicable for this missense variant under PALB2 VCEP
Evidence considered
- variant is missense
- PALB2 BP7 scope limited to synonymous/deep intronic or RNA evidence for those classes
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.35. BayesDel score = 0.236696.
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
1 / 1,613,900 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/657328/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649395-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23638074-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.104T…
- OncoKB ↗www.oncokb.org/gene/PALB2/L35P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.104T%3EC
- 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= 6.19617e-07; MAF= 0.00006%, 1/1613900 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4763e-07; MAF= 0.00008%, 1/1179760 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories) 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 = 0.01). REVEL score = 0.35. BayesDel score = 0.236696.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.