About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.841A>G, p.(Ile281Val)
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 in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
This is a missense variant, and the PALB2 VCEP applies BP1_Supporting to all missense variants because truncating variants are the primary 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: BP1 supporting, PM2 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 / 1,614,186 alleles
gnomAD v4.1: 1 / 1,614,186 alleles. Recorded AF 6.19507e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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
2 reported laboratory submissions
2 Uncertain significance.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55171918, n = 1 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: 2 met · 2 not met · 5 not assessed · 19 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.841A>G (p.Ile281Val) variant has been reported in ClinVar as uncertain significance by 2 clinical laboratories.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and far below the BS1 and BA1 thresholds.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational results are low or benign-leaning (REVEL 0.007; BayesDel -0.722292); however, under the PALB2 VCEP framework PP3 and BP4 are not applied for missense variants, while BP1_Supporting is applied to missense variation in this gene.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,186 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met. Details ▾Hide ▴
Rule
Frequency ≤1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v2.1.
- gnomAD v4 total AF 0.00006% (1/1
- 614
- 186 alleles).
- PALB2 PM2 threshold: ≤0.000333% in gnomAD v4.
Sources
BP1 SupportingThis is a missense variant, and the PALB2 VCEP applies BP1_Supporting to all missense variants because truncating variants are the primary established disease mechanism in PALB2. Details ▾Hide ▴
Rule
Apply to all missense variants
Evidence considered
- Variant consequence: missense p.(Ile281Val).
- PALB2 VCEP BP1 rule: apply to all missense variants.
Sources
Not met · 2 · evaluated, threshold not reached
BA1 The highest observed gnomAD v4 frequency is 0.00008%, 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
Evidence considered
- Highest observed gnomAD v4 subpopulation AF 0.00008%.
- PALB2 BA1 threshold: >0.1% in gnomAD v4.
Sources
BS1 The highest observed gnomAD v4 frequency is 0.00008% (1/1,180,022 alleles in European non-Finnish), 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
Evidence considered
- gnomAD v4 total AF 0.00006%
- highest subpopulation AF 0.00008%.
- PALB2 BS1 threshold: >0.01% in gnomAD v4.
Sources
Not assessed · 5 · no assessment recorded
PS4 No case-control data were identified showing this variant is enriched in affected individuals, so the PALB2 PS4 threshold cannot be evaluated. Details ▾Hide ▴
Rule
Case-control studies; p≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5
Evidence considered
- ClinVar shows two single-submitter uncertain significance submissions.
- PALB2 PS4 requires case-control evidence with p≤0.05 and OR/HR/RR threshold.
Still missing
- No variant-specific odds ratio
- relative risk
- or hazard ratio was identified.
- No exact-variant case-control study was identified.
Sources
PM3 No observations were identified showing this variant in trans with a pathogenic or likely pathogenic PALB2 variant in an individual with a recessive PALB2-associated phenotype, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Point-based PM3 framework for recessive PALB2 disease
Evidence considered
- PALB2 VCEP PM3 is point-based for recessive disease observations.
Still missing
- Phase-confirmed in trans observations were not identified.
- No Fanconi anemia-related case evidence was identified for this variant.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD: LOD/Bayes factor thresholds; AR: affected relative count thresholds
Evidence considered
- PALB2 VCEP PP1 requires quantified segregation evidence.
Still missing
- No pedigree data
- meioses
- LOD score
- or Bayes factor were identified.
Sources
BS2 No qualifying observations were identified in unaffected individuals that would allow BS2 point assignment under the PALB2 VCEP. Details ▾Hide ▴
Rule
BS2 is point-based; gnomAD is not sufficient
Evidence considered
- PALB2 VCEP BS2 is point-based and does not use population cohort data such as gnomAD.
Still missing
- No case-level unaffected-carrier evidence was identified.
- No BS2 point total could be calculated.
Sources
BS4 No family non-segregation data were identified for this variant, so the PALB2 BS4 LOD/Bayes factor thresholds cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes factor ≤0.053:1 for BS4_Strong; lower thresholds for BS4_Moderate/Supporting
Evidence considered
- PALB2 VCEP BS4 requires quantified non-segregation evidence.
Still missing
- Family-level segregation data with LOD score or Bayes factor were not identified.
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AAlthough loss of function is an established PALB2 disease mechanism, this variant is a missense substitution that does not fall into the PALB2 or generic PVS1 null-variant categories, and SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not applicable. Details ▾Hide ▴
Rule
Use PALB2 PVS1 decision tree; not in a PVS1-eligible variant bucket here
Evidence considered
- PALB2 is eligible for PVS1 at the gene level.
- Variant is not nonsense
- frameshift
- or canonical ±1
- 2 splice.
- SpliceAI max delta score 0.00.
Sources
PS1 N/APS1 is not applicable because the PALB2 VCEP does not use PS1 for missense changes, and no splice-based PS1 comparator evidence was identified. Details ▾Hide ▴
Rule
Use PALB2 PS1 splicing table; do not use for missense changes
Evidence considered
- PALB2 VCEP PS1: missense do not use
- splicing table applies in splice context.
- SpliceAI max delta score 0.00 does not suggest a splice-based PS1 scenario.
Sources
PS2 VCEPPS2 is not used by the PALB2 VCEP. Details ▾Hide ▴
PS3 VCEPPS3 is not used by the PALB2 VCEP for this variant context. Details ▾Hide ▴
PM1 VCEPPM1 is not used by the PALB2 VCEP because missense pathogenic variation is not an established PALB2 disease mechanism. Details ▾Hide ▴
PM4 VCEPThis is a missense variant, and the PALB2 VCEP does not apply PM4 to missense changes. Details ▾Hide ▴
VCEP rule
Do not use for in-frame insertions/deletions less than a single exon; use for stop-loss variants only
Evidence considered
- PALB2 VCEP marks PM4 as not applicable except stop-loss context.
Sources
PM5 N/APM5 is not applicable because the PALB2 VCEP does not use classic same-residue missense PM5 for missense variants, and the PM5 framework for PALB2 is limited to truncating or qualifying splice variants upstream of p.Tyr1183. Details ▾Hide ▴
Rule
Apply only to truncating or qualifying splice variants upstream of p.Tyr1183
Evidence considered
- PALB2 VCEP PM5 excludes missense changes.
- PM5 candidate review marked this gene as using a truncation-cutoff PM5 mode rather than classic same-residue missense PM5.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used by the PALB2 VCEP. Details ▾Hide ▴
PP2 VCEPPP2 is not used by the PALB2 VCEP because missense variation is not an established PALB2 disease mechanism. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice impact (max delta score 0.00), and the PALB2 VCEP specifies that PP3 should not be applied for missense variants, so PP3 is not applicable here. Available missense predictors are also low or benign-leaning (REVEL 0.007; BayesDel -0.722292), but PALB2 missense PP3 is not used under this framework. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥0.2 and is not applied for missense variants
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.007.
- BayesDel -0.722292.
- PALB2 VCEP PP3: do not use for missense variants.
Sources
PP4 VCEPPP4 is not used by the PALB2 VCEP for the autosomal dominant cancer predisposition setting. Details ▾Hide ▴
PP5 VCEPPP5 is not used by the PALB2 VCEP. Details ▾Hide ▴
BS3 VCEPBS3 is not used by the PALB2 VCEP for this variant context. Details ▾Hide ▴
BP2 VCEPBP2 is not used by the PALB2 VCEP. Details ▾Hide ▴
BP3 VCEPBP3 is not used by the PALB2 VCEP for this missense variant context. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact (max delta score 0.00), but the PALB2 VCEP specifies that BP4 should not be applied for missense variants, so BP4 is not applicable here. Details ▾Hide ▴
Rule
Splicing BP4 requires SpliceAI ≤0.1 and is not applied for missense variants
Evidence considered
- SpliceAI max delta score 0.00.
- PALB2 VCEP BP4: do not apply for missense variants.
Sources
BP5 VCEPBP5 is not used by the PALB2 VCEP. Details ▾Hide ▴
BP6 VCEPBP6 is not used by the PALB2 VCEP. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or deep intronic variants, and this variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA subrules for lack of aberrant splicing
Evidence considered
- Variant consequence: missense p.(Ile281Val).
- PALB2 VCEP BP7 applies to synonymous and deep intronic contexts.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.841A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Ile281Val)
- GRCh38
- chr16:23635705 T>C
- GRCh37
- chr16:23647026 T>C
- ClinVar
- 2748067, 530108
- COSMIC
- COSV55171918
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
1 / 1,614,186 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 / 1,614,186 alleles · 0 hom
| European (non-Finnish)1 / 1,180,022 | 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= 6.19507e-07; MAF= 0.00006%, 1/1614186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47442e-07; MAF= 0.00008%, 1/1180022 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.007
- BayesDel
- -0.722
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact (max delta score 0.00), and the PALB2 VCEP specifies that PP3 should not be applied for missense variants, so PP3 is not applicable here. Available missense predictors are also low or benign-leaning (REVEL 0.007; BayesDel -0.722292), but PALB2 missense PP3 is not used under this framework. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥0.2 and is not applied for missense variants
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL 0.007.
- BayesDel -0.722292.
- PALB2 VCEP PP3: do not use for missense variants.
Sources
BP4 N/ASpliceAI predicts no significant splice impact (max delta score 0.00), but the PALB2 VCEP specifies that BP4 should not be applied for missense variants, so BP4 is not applicable here. Details ▾Hide ▴
Rule
Splicing BP4 requires SpliceAI ≤0.1 and is not applied for missense variants
Evidence considered
- SpliceAI max delta score 0.00.
- PALB2 VCEP BP4: do not apply for missense variants.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, and this variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA subrules for lack of aberrant splicing
Evidence considered
- Variant consequence: missense p.(Ile281Val).
- PALB2 VCEP BP7 applies to synonymous and deep intronic contexts.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.007. BayesDel score = -0.722292.
9 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
-
PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.No paper-specific finding is recorded.
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
-
PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
-
PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.Moyer VA et al. · 2014No paper-specific finding is recorded.
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PMID 24366402 ↗Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.2014No paper-specific finding is recorded.
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PMID 24432435 ↗PMID:24432435Nelson HD et al. · 2013No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,186 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
2 Uncertain significance
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/530108/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647026-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635705-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.841A…
- OncoKB ↗www.oncokb.org/gene/PALB2/I281V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120585706
- 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= 6.19507e-07; MAF= 0.00006%, 1/1614186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47442e-07; MAF= 0.00008%, 1/1180022 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 530108)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.007. BayesDel score = -0.722292.
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; COSV55171918, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.