About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.194C>T, p.(Pro65Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This variant is a missense change, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variation is thought to be very uncommon in this gene.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting; no rule matched the adjudicated criteria.
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
93 / 1,612,258 alleles
gnomAD v4.1: 93 / 1,612,258 alleles. Recorded AF 5.76831e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59565e-05; MAF= 0.00460%, 13/282876 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.28908e-05; MAF= 0.00929%, 12/129184 alleles, homozygotes = 0); grpmax FAF= 5.377e-05.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105056546, n = 2 times).
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: 1 met · 5 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 NM_024675.4:c.194C>T (NP_078951.2:p.(Pro65Leu), p.(P65L)) variant has been reported in ClinVar, but no expert panel classification is available.
This variant is present in gnomAD v4.1 at 0.00577% (93/1612258 alleles) with a highest observed population frequency of 0.00961%, which is below the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.
SpliceAI predicts no significant splice impact (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193), although the PALB2 expert specification does not use missense computational predictors for PP3 or BP4 in this setting.
No criteria match.
Met · 1
BP1 SupportingThis variant is a missense change, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variation is thought to be very uncommon in this gene. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- The variant is p.(Pro65Leu)
- a missense substitution.
- PALB2 BP1 is specified to apply to all missense variants.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 PALB2 loss of function is an established disease mechanism, but this variant is a missense substitution and does not fall into the generic null-variant categories for PVS1. It is not a nonsense, frameshift, or canonical ±1,2 splice-site variant, and no RNA evidence showing a qualifying loss-of-function splice effect was identified. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- PALB2 is PVS1-eligible at the gene level.
- The variant-level PVS1 assessment placed this change outside the generic PVS1 null-variant buckets.
- SpliceAI max delta score is 0.00.
Still missing
- Variant-specific RNA evidence demonstrating a qualifying loss-of-function splice defect was not identified.
Sources
PM2 This variant is present in gnomAD v4.1 at 0.00577%, which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset for PM2_Supporting.
Evidence considered
- gnomAD v4.1 total AF is 5.76831e-05 (0.00577%
- 93/1612258 alleles).
- PALB2 PM2 is only applied at Supporting strength when frequency is ≤ 0.000333% in gnomAD v4.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2 for splice-based use. REVEL is 0.029 and BayesDel is -0.55193, but the PALB2 expert specification does not use missense computational predictors for PP3. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥ 0.2; missense PP3 is otherwise not used.
Evidence considered
- SpliceAI max delta score is 0.00.
- REVEL score is 0.029.
- BayesDel score is -0.55193.
- PALB2 PP3 for missense changes is limited to splice prediction with SpliceAI ≥ 0.2.
Sources
BA1 The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > 0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 highest observed population AF is 9.6083e-05 (0.00961%).
- PALB2 BA1 requires grpmax filtering AF > 0.1% in gnomAD v4.
Sources
BS1 The highest observed gnomAD v4.1 population frequency is 0.00961%, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF > 0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 highest observed population AF is 9.6083e-05 (0.00961%).
- PALB2 BS1 requires grpmax filtering AF > 0.01% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 The variant has been reported in clinical databases and publications, but the available evidence does not provide a qualifying variant-specific case-control estimate with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5, so PS4 cannot be assigned. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤ 0.05 AND OR/HR/RR ≥ 3 or lower 95% CI ≥ 1.5.
Evidence considered
- ClinVar contains submissions for this variant.
- Published case-observation and case-control literature was identified
- but no qualifying variant-specific PS4 statistics were available in the retrieved evidence.
Still missing
- A qualifying variant-specific case-control analysis meeting the PALB2 PS4 threshold was not identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 points cannot be assigned. Details ▾Hide ▴
Rule
PM3 requires Fanconi anemia point-based evidence, with 1 point for PM3_Supporting and 2 points for PM3.
Evidence considered
- PALB2 PM3 is point-based for Fanconi anemia cases.
- No qualifying in trans observations were available in the retrieved evidence.
Still missing
- Biallelic case data with confirmed phase and phenotype were not identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated. Details ▾Hide ▴
Rule
For AD disease, PP1_Supporting requires LOD ≥ 0.3 or LR ≥ 2:1; higher tiers require larger values.
Evidence considered
- PALB2 PP1 requires quantitative co-segregation evidence.
- A segregation-themed paper was identified
- but no variant-specific PP1 calculation was available in the retrieved evidence.
Still missing
- Variant-specific segregation data with LOD score or likelihood ratio analysis were not identified.
Sources
BS2 No qualifying observations were identified in healthy adults or other point-based PALB2 BS2 evidence, so BS2 cannot be assigned. Details ▾Hide ▴
Rule
BS2 point-based framework: 1 point for Supporting, 2 for Moderate, and 4 for Strong.
Evidence considered
- PALB2 BS2 requires point-based evidence and should not be assigned from population databases alone.
- No qualifying BS2 observations were available in the retrieved evidence.
Still missing
- Qualifying BS2 observations with the PALB2 point framework were not identified.
Sources
BS4 No quantitative segregation or lack-of-segregation data were identified for this variant, so the PALB2 BS4 thresholds based on LOD score or likelihood ratio cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1 for BS4_Strong; lower tiers also require quantitative data.
Evidence considered
- PALB2 BS4 requires quantitative segregation evidence.
- A segregation-themed paper was identified
- but no variant-specific BS4 calculation was available in the retrieved evidence.
Still missing
- Variant-specific segregation data with quantitative LOD or likelihood ratio analysis were not identified.
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a missense variant, and the PALB2 expert specification states that PS1 should not be used for missense changes. No qualifying splice-based PS1 evidence was identified. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: see PALB2 PS1 table.
Evidence considered
- PALB2 PS1 is not used for missense changes.
- SpliceAI max delta score is 0.00
- so no splice-based lead was identified.
Still missing
- A qualifying PALB2 PS1 splice-table match was not identified.
Sources
PS2 VCEPPS2 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists PS2 as not applicable.
Sources
PS3 VCEPPS3 is not used in the PALB2 expert specification for this context. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists PS3 as not applicable.
- No variant-specific reviewed functional evidence was identified in the retrieved OncoKB summary.
Sources
PM1 VCEPPM1 is not used in the PALB2 expert specification because pathogenic missense variation is not established as a disease mechanism for PALB2. Details ▾Hide ▴
VCEP rule
Do not use for PALB2 missense variants.
Evidence considered
- The PALB2 specification lists PM1 as not applicable.
- Cancer Hotspots did not identify a statistically significant hotspot at this residue.
Sources
PM4 VCEPThis is a missense variant, and the PALB2 specification restricts PM4 to stop-loss variants rather than missense changes. Details ▾Hide ▴
VCEP rule
Use for stop-loss variants only.
Evidence considered
- PALB2 PM4 is not used for missense variants.
- The variant is p.(Pro65Leu)
- a missense substitution.
Sources
PM5 N/AThe PALB2 PM5 rule is repurposed for truncating or qualifying splice variants upstream of p.Tyr1183 and is not used for missense changes. This missense variant is therefore not eligible for PM5. Details ▾Hide ▴
Rule
Use as PM5_Supporting for truncating or qualifying splice variants upstream of p.Tyr1183; do not use for missense changes.
Evidence considered
- The PM5 candidate review identified a truncation-cutoff PALB2 framework rather than classic same-residue missense PM5.
- The variant is p.(Pro65Leu)
- a missense substitution.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists PM6 as not applicable.
Sources
PP2 VCEPPP2 is not used in the PALB2 expert specification because missense variation is not established as a common disease mechanism for PALB2. Details ▾Hide ▴
VCEP rule
Do not use.
Evidence considered
- The PALB2 specification lists PP2 as not applicable.
Sources
PP4 VCEPPP4 is not used in the PALB2 expert specification because the associated cancer phenotypes are genetically heterogeneous and not sufficiently specific for this rule. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists PP4 as not applicable.
Sources
PP5 VCEPPP5 is not used in the PALB2 expert specification. Details ▾Hide ▴
BS3 VCEPBS3 is not used in the PALB2 expert specification for this context. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists BS3 as not applicable.
Sources
BP2 VCEPBP2 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists BP2 as not applicable.
Sources
BP3 VCEPBP3 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists BP3 as not applicable.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193); however, the PALB2 expert specification states that BP4 should not be applied for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing BP4 requires SpliceAI ≤ 0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.00.
- REVEL score is 0.029.
- BayesDel score is -0.55193.
- PALB2 BP4 is not used for missense variants.
Sources
BP5 VCEPBP5 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- The PALB2 specification lists BP5 as not applicable.
Sources
BP6 VCEPBP6 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- The PALB2 specification lists BP6 as not applicable.
Sources
BP7 N/ABP7 is intended for synonymous and qualifying deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence showing no aberrant splicing for those variant classes.
Evidence considered
- The variant is p.(Pro65Leu)
- a missense substitution.
- PALB2 BP7 is specified for synonymous and deep intronic variants or RNA evidence for those variant classes.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.194C>T
- Protein (HGVS p.)
- NP_078951.2:p.(Pro65Leu)
- GRCh38
- chr16:23637867 G>A
- GRCh37
- chr16:23649188 G>A
- ClinVar
- 3228000, 128124
- COSMIC
- COSV105056546
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
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
93 / 1,612,258 alleles
AF 5.77e-05 · 0 homozygotes · FAF 5.96e-05
gnomAD v2.1
13 / 282,876 alleles
AF 4.6e-05 · 0 homozygotes · FAF 5.38e-05
By genetic ancestry
gnomAD v4.1
AF 5.8e-05 · 93 / 1,612,258 alleles · 0 hom · FAF 6e-05
| Remaining individuals6 / 62,446 | 9.6e-05 |
| European (non-Finnish)85 / 1,178,446 | 7.2e-05 |
| East Asian1 / 44,884 | 2.2e-05 |
| African/African American1 / 74,870 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4.6e-05 · 13 / 282,876 alleles · 0 hom · FAF 5.4e-05
| European (non-Finnish)12 / 129,184 | 9.3e-05 |
| East Asian1 / 19,954 | 5e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.76831e-05; MAF= 0.00577%, 93/1612258 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.6083e-05; MAF= 0.00961%, 6/62446 alleles, homozygotes = 0); grpmax FAF= 5.965e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59565e-05; MAF= 0.00460%, 13/282876 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.28908e-05; MAF= 0.00929%, 12/129184 alleles, homozygotes = 0); grpmax FAF= 5.377e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.029
- BayesDel
- -0.552
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2 for splice-based use. REVEL is 0.029 and BayesDel is -0.55193, but the PALB2 expert specification does not use missense computational predictors for PP3. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥ 0.2; missense PP3 is otherwise not used.
Evidence considered
- SpliceAI max delta score is 0.00.
- REVEL score is 0.029.
- BayesDel score is -0.55193.
- PALB2 PP3 for missense changes is limited to splice prediction with SpliceAI ≥ 0.2.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and missense predictor scores are low (REVEL 0.029; BayesDel -0.55193); however, the PALB2 expert specification states that BP4 should not be applied for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing BP4 requires SpliceAI ≤ 0.1, but do not apply for missense variants.
Evidence considered
- SpliceAI max delta score is 0.00.
- REVEL score is 0.029.
- BayesDel score is -0.55193.
- PALB2 BP4 is not used for missense variants.
Sources
BP7 N/ABP7 is intended for synonymous and qualifying deep intronic variants, whereas this variant is a missense substitution. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or RNA evidence showing no aberrant splicing for those variant classes.
Evidence considered
- The variant is p.(Pro65Leu)
- a missense substitution.
- PALB2 BP7 is specified for synonymous and deep intronic variants or RNA evidence for those variant classes.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.029. BayesDel score = -0.55193.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25356972 ↗BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.Zhen DB et al. · 2015No paper-specific finding is recorded.
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PMID 26564480 ↗Mutation analysis of PALB2 gene in French breast cancer families.No paper-specific finding is recorded.
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PMID 28779002 ↗Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.Decker B et al. · 2017No paper-specific finding is recorded.
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PMID 31586400 ↗A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.No paper-specific finding is recorded.
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PMID 33139182 ↗PALB2 Variants: Protein Domains and Cancer Susceptibility.No paper-specific finding is recorded.
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PMID 34326862 ↗Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.No paper-specific finding is recorded.
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PMID 20301425 ↗PMID:20301425No paper-specific finding is recorded.
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PMID 20582465 ↗PALB2 analysis in BRCA2-like families.Adank MA et al. · 2011No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
93 / 1,612,258 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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/128124/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649188-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23637867-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.194C…
- OncoKB ↗www.oncokb.org/gene/PALB2/P65L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120588042
- 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= 5.76831e-05; MAF= 0.00577%, 93/1612258 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.6083e-05; MAF= 0.00961%, 6/62446 alleles, homozygotes = 0); grpmax FAF= 5.965e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59565e-05; MAF= 0.00460%, 13/282876 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.28908e-05; MAF= 0.00929%, 12/129184 alleles, homozygotes = 0); grpmax FAF= 5.377e-05.
ClinVar
This variant is present in ClinVar (Variation ID: 128124); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.029. BayesDel score = -0.55193.
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; COSV105056546, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.