About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1960A>G, p.(Ile654Val)
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 substitution, and the PALB2 expert specification applies BP1 to all missense variants because established pathogenic PALB2 variation is predominantly truncating.
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
7 / 1,614,140 alleles
gnomAD v4.1: 7 / 1,614,140 alleles. Recorded AF 4.33667e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96324e-06; MAF= 0.00080%, 2/251154 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53296e-05; MAF= 0.00653%, 2/30614 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
9 reported laboratory submissions
8 Uncertain significance · 1 Likely benign.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 4 not met · 5 not assessed · 18 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.1960A>G (p.Ile654Val) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission, and no expert panel classification was identified.
This variant is present in gnomAD v4 at 0.00043% overall (7/1,614,140 alleles) with a highest observed population frequency of 0.00769% in South Asians, which is above the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 threshold of 0.01%.
Under the PALB2 expert specification, BP1 is met because this is a missense variant in a gene for which established pathogenic variation is predominantly truncating.
SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01); REVEL is 0.043 and BayesDel is -0.826097, although the PALB2 expert specification does not use PP3 or BP4 for missense prediction alone.
No criteria match.
Met · 1
BP1 SupportingThis variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because established pathogenic PALB2 variation is predominantly truncating. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.4:c.1960A>G predicts NP_078951.2:p.(Ile654Val) / p.(I654V).
- PALB2 CSPEC states BP1 applies to all missense variants.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a predicted loss-of-function variant, and the generic PVS1 scaffold specifically notes that it does not fall within the usual null-variant categories, so PVS1 is not met. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- PALB2 has PVS1 eligibility in the gene-level framework because loss of function is an established mechanism.
- Variant-level PVS1 assessment states this variant is not nonsense
- frameshift
- or canonical ±1/2 splice.
- Protein consequence is p.(Ile654Val) / p.(I654V).
Sources
PM2 This variant is present in gnomAD v4 at 0.00043% (7/1,614,140 alleles), 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 total AF 0.00043% (7/1
- 614
- 140 alleles)
- no homozygotes.
- gnomAD v2 total AF 0.00080% (2/251
- 154 alleles)
Sources
BA1 The highest observed gnomAD v4 population frequency is 0.00769%, which is well 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 highest observed population AF 0.00769% in South Asians.
- gnomAD v4 total AF 0.00043%.
Sources
BS1 The highest observed gnomAD v4 population frequency is 0.00769% in South Asians, 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 total AF 0.00043% (7/1
- 614
- 140 alleles).
- Highest observed population AF 0.00769% in South Asians.
Sources
Not assessed · 5 · no assessment recorded
PS4 No qualifying case-control study showing significant enrichment of this exact variant in affected individuals was identified, so PS4 cannot be applied. Details ▾Hide ▴
Rule
Case-control studies with p-value ≤ 0.05 and OR/HR/RR ≥ 3 or lower 95% CI ≥ 1.5.
Evidence considered
- ClinVar shows mostly uncertain significance submissions and no expert panel classification.
- No case-control result for this exact variant meeting PALB2 PS4 criteria was identified.
Still missing
- A case-control study for this exact variant meeting the PALB2 PS4 threshold is needed.
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 cannot be assessed. Details ▾Hide ▴
Rule
PM3 is assigned from Fanconi anemia point totals.
Evidence considered
- PALB2 CSPEC uses a Fanconi anemia point-based PM3 framework.
- No qualifying in trans Fanconi anemia observations were identified for this variant.
Still missing
- Phase-confirmed biallelic observations in Fanconi anemia are needed to score PM3.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
PP1 strength depends on LOD score or Bayes factor thresholds.
Evidence considered
- PALB2 CSPEC requires quantitative segregation evidence for PP1.
- No qualifying family segregation data were identified for this variant.
Still missing
- Family segregation data with a calculable LOD score or Bayes factor are needed to assess PP1.
Sources
BS2 No qualifying observations in healthy adult individuals or other evidence meeting the PALB2 BS2 point-based framework were identified. Details ▾Hide ▴
Rule
BS2 is assigned from Fanconi anemia BS2 point totals.
Evidence considered
- PALB2 CSPEC uses a point-based BS2 framework.
- No qualifying BS2 observations were identified for this variant.
Still missing
- Documented qualifying unaffected adult observations under the PALB2 BS2 point system are needed.
Sources
BS4 No quantitative non-segregation data were identified, so the PALB2 BS4 thresholds cannot be evaluated for this variant. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1 for BS4_Strong, with lower thresholds for Moderate and Supporting.
Evidence considered
- PALB2 CSPEC requires quantitative segregation evidence for BS4.
- Available records did not provide family non-segregation data for this variant.
Still missing
- Family segregation data with LOD score or Bayes factor are needed to assess BS4.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThe PALB2 expert specification directs PS1 to a splicing table, and this variant has no predicted splice effect by SpliceAI (maximum delta score 0.01), so PS1 is not applicable on the available evidence. Details ▾Hide ▴
Rule
Use PALB2 PS1 Splicing table.
Evidence considered
- PALB2 CSPEC directs PS1 to the PALB2 PS1 Splicing table.
- SpliceAI max delta score 0.01 indicates no predicted significant splice impact.
Sources
PS2 VCEPPS2 is not used in this PALB2 expert specification. Details ▾Hide ▴
PS3 VCEPPS3 is not used for this PALB2 variant under the available expert specification, and no variant-specific reviewed functional study was identified in the retrieved evidence. Details ▾Hide ▴
PM1 VCEPPM1 is not used for PALB2 missense variants because missense pathogenic variation is not an established disease mechanism in this expert specification. Details ▾Hide ▴
VCEP rule
Do not use for PALB2 missense variants.
Evidence considered
- PALB2 CSPEC marks PM1 as not applicable.
- Cancer Hotspots did not identify this residue as a statistically significant hotspot.
Sources
PM4 VCEPThis is a missense substitution, and the PALB2 expert specification does not use PM4 for this variant type. Details ▾Hide ▴
VCEP rule
Do not use for in-frame insertions or deletions less than a single exon; use for stop-loss variants only.
Evidence considered
- PALB2 c.1960A>G predicts p.(Ile654Val)
- a missense change.
- PALB2 CSPEC states PM4 is not applicable except for stop-loss variants.
Sources
PM5 N/AThe PALB2 PM5 rule is a truncation-cutoff framework and not a classic same-residue missense rule, and the PM5 candidate review marked this missense variant as not eligible for classic PM5 assessment. Details ▾Hide ▴
Rule
Apply to qualifying truncating or qualifying splice variants with premature termination codons upstream of p.Tyr1183.
Evidence considered
- PM5 candidate review marked eligible_for_classic_pm5_search as false.
- PALB2 CSPEC PM5 applies to qualifying truncating or splice variants expected to create premature termination codons upstream of p.Tyr1183.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the PALB2 expert specification. Details ▾Hide ▴
VCEP rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 CSPEC marks PM6 as not applicable.
Sources
PP2 VCEPPP2 is not used for PALB2 because missense variation is not an established disease mechanism in this expert specification. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the PALB2 expert specification states PP3 should not be applied for missense variants unless there is predicted splice impact, so PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≥ 0.2.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.043.
- BayesDel score -0.826097.
- PALB2 CSPEC states PP3 is not used for missense prediction and is reserved for splice prediction with SpliceAI ≥ 0.2.
Sources
PP4 VCEPPP4 is not used for PALB2-related cancer predisposition in this expert specification because the phenotype is not sufficiently specific. Details ▾Hide ▴
VCEP rule
Do not use for AD disorder.
Evidence considered
- PALB2 CSPEC marks PP4 as not applicable for the autosomal dominant condition.
Sources
PP5 VCEPPP5 is not used in this PALB2 expert specification. Details ▾Hide ▴
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 CSPEC marks PP5 as not applicable for this VCEP.
Sources
BS3 VCEPNo PALB2 protein functional assay framework supporting BS3 use was identified for this missense variant in the expert specification. Details ▾Hide ▴
BP2 VCEPBP2 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP3 VCEPBP3 is not used in this PALB2 expert specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the PALB2 expert specification states BP4 should not be applied for missense variants, so BP4 is not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≤ 0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01.
- PALB2 CSPEC states BP4 is not used for missense variants.
Sources
BP5 VCEPBP5 is not used in the PALB2 expert specification. Details ▾Hide ▴
BP6 VCEPBP6 is not used in this PALB2 expert specification. Details ▾Hide ▴
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 CSPEC marks BP6 as not applicable for this VCEP.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based extensions may apply to those variant classes.
Evidence considered
- PALB2 c.1960A>G predicts a missense change
- p.(Ile654Val).
- PALB2 CSPEC BP7 guidance is for synonymous and deep intronic variants.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1960A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Ile654Val)
- GRCh38
- chr16:23630194 T>C
- GRCh37
- chr16:23641515 T>C
- ClinVar
- 234115
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
7 / 1,614,140 alleles
AF 4.34e-06 · 0 homozygotes · FAF 3.59e-05
gnomAD v2.1
2 / 251,154 alleles
AF 7.96e-06 · 0 homozygotes · FAF 1.08e-05
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,614,140 alleles · 0 hom · FAF 3.6e-05
| South Asian7 / 91,084 | 7.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 8e-06 · 2 / 251,154 alleles · 0 hom · FAF 1.1e-05
| South Asian2 / 30,614 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33667e-06; MAF= 0.00043%, 7/1614140 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 7.68521e-05; MAF= 0.00769%, 7/91084 alleles, homozygotes = 0); grpmax FAF= 3.587e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96324e-06; MAF= 0.00080%, 2/251154 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53296e-05; MAF= 0.00653%, 2/30614 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.043
- BayesDel
- -0.826
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the PALB2 expert specification states PP3 should not be applied for missense variants unless there is predicted splice impact, so PP3 is not applicable. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≥ 0.2.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.043.
- BayesDel score -0.826097.
- PALB2 CSPEC states PP3 is not used for missense prediction and is reserved for splice prediction with SpliceAI ≥ 0.2.
Sources
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but the PALB2 expert specification states BP4 should not be applied for missense variants, so BP4 is not applicable here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing only if SpliceAI ≤ 0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01.
- PALB2 CSPEC states BP4 is not used for missense variants.
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based extensions may apply to those variant classes.
Evidence considered
- PALB2 c.1960A>G predicts a missense change
- p.(Ile654Val).
- PALB2 CSPEC BP7 guidance is for synonymous and deep intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.043. BayesDel score = -0.826097.
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 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
-
PMID 27648926 ↗Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.Silvestri V et al. · 2017No paper-specific finding is recorded.
-
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.
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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.
-
PMID 21279724 ↗Mutations in Fanconi anemia genes and the risk of esophageal cancer.Akbari MR et al. · 2011No paper-specific finding is recorded.
-
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
7 / 1,614,140 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
8 Uncertain significance · 1 Likely benign
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/234115/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641515-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23630194-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1960…
- OncoKB ↗www.oncokb.org/gene/PALB2/I654V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1960A%3EG
- 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= 4.33667e-06; MAF= 0.00043%, 7/1614140 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 7.68521e-05; MAF= 0.00769%, 7/91084 alleles, homozygotes = 0); grpmax FAF= 3.587e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96324e-06; MAF= 0.00080%, 2/251154 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53296e-05; MAF= 0.00653%, 2/30614 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 234115)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.043. BayesDel score = -0.826097.
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.