About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2027T>C, p.(Ile676Thr)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
Population frequency is above the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BA1 threshold of 0.1%.
BS1Strong
BS1 · strong
Population frequency is above the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BS1 threshold of 0.01%.
BP1Supporting
BP1 · supporting
This variant is a missense change, and the PALB2 VCEP applies BP1_Supporting to all missense variants because pathogenic PALB2 variation is predominantly truncating and true pathogenic missense variants are considered very rare.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BP6 supporting benign, BP1 supporting, BS1 strong, BA1 stand-alone benign; maps to 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
230 / 1,614,160 alleles
gnomAD v4.1: 230 / 1,614,160 alleles. Recorded AF 0.000142489. Recorded homozygote count 2.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000728337; MAF= 0.07283%, 206/282836 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.00578606; MAF= 0.57861%, 205/35430 alleles, homozygotes = 1); grpmax FAF= 0.00515383.
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.
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: 4 met · 2 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 c.2027T>C (p.Ile676Thr) variant has been reported in ClinVar as Benign, including a reviewed expert panel classification.
This variant is present in gnomAD v4.1 with an overall allele frequency of 0.01425% (230/1614160) and a highest observed population frequency of 0.37653% (226/60022 alleles in the Admixed American population), which is above the PALB2 BA1 threshold of 0.1% and the BS1 threshold of 0.01%.
In silico data do not support a splice effect, with a SpliceAI maximum delta score of 0.02; REVEL is 0.003 and BayesDel is -0.705338, but the PALB2 VCEP does not use PP3 or BP4 for missense variants.
No criteria match.
Met · 4
BA1 Stand alonePopulation frequency is above the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BA1 threshold of 0.1%. Details ▾Hide ▴
Rule
Grpmax Filtering AF > 0.1% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 0.0037652860617773485 (0.37653%).
- PALB2 BA1 threshold is grpmax filtering AF > 0.1%.
Sources
BS1 StrongPopulation frequency is above the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.37653% (226/60022 alleles in Admixed American), which is above the BS1 threshold of 0.01%. Details ▾Hide ▴
Rule
Grpmax Filtering AF > 0.01% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 0.0037652860617773485 (0.37653%).
- PALB2 BS1 threshold is grpmax filtering AF > 0.01%.
Sources
BP1 SupportingThis variant is a missense change, and the PALB2 VCEP applies BP1_Supporting to all missense variants because pathogenic PALB2 variation is predominantly truncating and true pathogenic missense variants are considered very rare. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.3:c.2027T>C predicts NP_078951.2:p.(Ile676Thr)
- a missense variant.
- PALB2 VCEP BP1 rule applies to all missense variants.
Sources
BP6 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign. Details ▾Hide ▴
Not met · 2 · evaluated, threshold not reached
PVS1 This variant is a missense substitution and does not fall within the PALB2 or generic PVS1 null-variant categories. Available evidence does not show a predicted loss-of-function consequence, and the generic PVS1 scaffold states that this variant is not a nonsense, frameshift, or canonical ±1,2 splice variant. Details ▾Hide ▴
Rule
Use PALB2 PVS1 decision tree for qualifying loss-of-function variants.
Evidence considered
- PALB2 loss of function is an established disease mechanism at the gene level.
- The variant-level PVS1 assessment states that c.2027T>C is outside the default generic null-variant buckets.
- The variant is annotated as p.(Ile676Thr)
- a missense change.
Sources
PM2 Population frequency is above the PALB2 PM2_Supporting threshold. In gnomAD v4.1, the overall allele frequency is 0.01425% (230/1614160), and the highest observed population frequency is 0.37653% (226/60022 in Admixed American), both above the PM2 threshold of 0.000333%. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset for PM2_Supporting.
Evidence considered
- gnomAD v4.1 total AF = 0.00014248897259255589 (0.01425%).
- gnomAD v4.1 best subpopulation AF = 0.0037652860617773485 (0.37653%).
- PALB2 PM2 threshold is frequency ≤ 0.000333%.
Sources
Not assessed · 5 · no assessment recorded
PS4 No case-control study or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls. Available evidence does not support applying PS4 at this time. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤ 0.05 and odds ratio, hazard ratio, or relative risk ≥ 3 or lower 95% CI ≥ 1.5.
Evidence considered
- PALB2 VCEP PS4 requires case-control evidence.
- ClinVar reporting alone does not satisfy the PALB2 PS4 rule.
Still missing
- No qualifying case-control statistics with p-value and effect size meeting the PALB2 PS4 threshold were identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other data meeting the PALB2 PM3 point-based framework. Details ▾Hide ▴
Rule
PM3_Supporting = 1 point; PM3 = 2 points; PM3_Strong ≥ 4 points; PM3_VeryStrong ≥ 8 points.
Evidence considered
- PALB2 VCEP PM3 is point based for recessive disease evidence
- no qualifying observations were available.
Still missing
- No phase-confirmed in trans observations or PM3 point assignments were identified.
Sources
PP1 No segregation data were identified for this variant. The PALB2 VCEP requires quantitative segregation evidence, and no LOD score or likelihood ratio meeting PP1 thresholds was available. Details ▾Hide ▴
Rule
AD condition: LOD ≥ 0.3 for Supporting, ≥ 0.60 for Moderate, ≥ 1.26 for Strong.
Evidence considered
- PALB2 VCEP PP1 requires quantitative segregation evidence
- none was available for this variant.
Still missing
- No family-based segregation analysis with LOD score or likelihood ratio was identified.
Sources
BS2 No qualifying observations were identified in healthy adults that could be scored under the PALB2 BS2 point-based framework. Population database counts alone are not sufficient for BS2 in this specification. Details ▾Hide ▴
Rule
BS2_Supporting = 1 point; BS2_Moderate = 2 points; BS2 = 4 points.
Evidence considered
- PALB2 VCEP BS2 requires point-based evidence and does not use population cohorts such as gnomAD for this criterion.
Still missing
- No phenotype-qualified healthy adult observations or BS2 point assignments were identified.
Sources
BS4 No quantitative non-segregation data were identified for this variant. The PALB2 VCEP requires LOD score or likelihood ratio evidence, and no family-based data meeting the BS4 thresholds were available. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1 for Strong; lower thresholds for Moderate or Supporting.
Evidence considered
- PALB2 VCEP BS4 requires quantitative family data
- none were available for this variant.
Still missing
- Formal segregation or non-segregation data with LOD score or likelihood ratio were not identified.
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is a missense change, and the PALB2 VCEP does not use PS1 for missense variants. No evidence was identified that this substitution matches a qualifying PALB2 splice-based PS1 table entry. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: see PALB2 PS1 table.
Evidence considered
- PALB2 VCEP PS1 instruction states missense do not use.
- SpliceAI max delta score = 0.02
- which does not suggest a qualifying splice effect.
Sources
PS2 N/APS2 is not used for PALB2 in this VCEP framework. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP marks PS2 as not applicable.
Sources
PS3 N/APS3 is not used for PALB2 protein functional studies in this framework, and no qualifying RNA evidence establishing a damaging splice effect was identified to support an RNA-based loss-of-function code instead. Details ▾Hide ▴
Rule
For RNA use PVS1_O and modulate strength based on assay quality; PS3 is not otherwise used here.
Evidence considered
- PALB2 VCEP marks PS3 as not applicable in this framework.
Still missing
- No qualifying RNA study showing an abnormal splice outcome was identified.
Sources
PM1 N/APM1 is not used for PALB2 because missense pathogenic variation is not an established disease mechanism in this gene-specific framework. Details ▾Hide ▴
PM4 N/AThis is a missense variant, not a stop-loss variant. The PALB2 VCEP does not use PM4 for missense changes. Details ▾Hide ▴
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.2027T>C predicts p.(Ile676Thr)
- a missense change.
Sources
PM5 N/AThis variant is a missense change, and the PALB2 VCEP does not use PM5 for missense variants. The PALB2 PM5 adaptation is limited to qualifying truncating or splice variants expected to behave as loss-of-function alleles. Details ▾Hide ▴
Rule
Use as PM5_Supporting for qualifying truncating or splice variants; do not use for missense changes.
Evidence considered
- PALB2 VCEP PM5 instruction states not to use for missense changes.
Sources
PM6 N/APM6 is not used for PALB2 in this VCEP framework. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 VCEP marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used for PALB2 because missense variation is not an established pathogenic mechanism in this gene-specific framework. Details ▾Hide ▴
PP3 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2. In addition, the PALB2 VCEP does not apply PP3 to missense variants. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply PP3 under the PALB2 missense rule. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via splicing (SpliceAI ≥ 0.2).
Evidence considered
- SpliceAI max delta score = 0.02.
- REVEL = 0.003.
- BayesDel = -0.705338.
- PALB2 VCEP PP3 instruction: missense do not use.
Sources
PP4 N/APP4 is not used for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for this gene under the PALB2 VCEP framework. Details ▾Hide ▴
Rule
Do not use for AD disorder.
Evidence considered
- PALB2 VCEP marks PP4 as not applicable for the dominant disorder context.
Sources
PP5 N/APP5 is not used by this VCEP. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 VCEP marks PP5 as not applicable.
Sources
BS3 N/AThe PALB2 VCEP does not use BS3 for protein functional studies in this framework, and no qualifying RNA evidence showing a normal transcript was identified to support an RNA-based benign code instead. Details ▾Hide ▴
Rule
For RNA use BP7_O and modulate strength based on assay quality; BS3 is not otherwise used here.
Evidence considered
- PALB2 VCEP marks BS3 as not applicable for protein-level use in this framework.
Still missing
- No RNA study demonstrating lack of aberrant splicing was identified.
Sources
BP2 N/ABP2 is not used for PALB2 in this VCEP framework. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, and BP3 is not used for PALB2 in this VCEP framework. Details ▾Hide ▴
Rule
Do not use.
Evidence considered
- NM_024675.3:c.2027T>C is a missense substitution.
- PALB2 VCEP marks BP3 as not applicable.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 VCEP does not apply BP4 to missense variants, so BP4 is not used here. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply BP4 under the PALB2 missense rule. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via splicing (SpliceAI ≤ 0.1); do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- REVEL = 0.003.
- BayesDel = -0.705338.
- PALB2 VCEP BP4 instruction: missense do not use.
Sources
BP5 N/ABP5 is not used for PALB2 in this VCEP framework. Details ▾Hide ▴
BP7 N/AThis is not a synonymous or deep intronic variant, and no RNA study showing a normal transcript was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based extensions require observed lack of aberrant RNA defect.
Evidence considered
- NM_024675.3:c.2027T>C is a missense exonic substitution.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.2027T>C
- Protein (HGVS p.)
- NP_078951.2:p.(Ile676Thr)
- GRCh38
- chr16:23630127 A>G
- GRCh37
- chr16:23641448 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
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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
230 / 1,614,160 alleles
AF 0.000142 · 2 homozygotes · FAF 0.00336
gnomAD v2.1
206 / 282,836 alleles
AF 0.000728 · 1 homozygotes · FAF 0.00515
By genetic ancestry
gnomAD v4.1
AF 0.00014 · 230 / 1,614,160 alleles · 2 hom · FAF 0.0034
| Admixed American226 / 60,022 | 0.00382 hom |
| Remaining individuals3 / 62,504 | 4.8e-05 |
| East Asian1 / 44,888 | 2.2e-05 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 0.00073 · 206 / 282,836 alleles · 1 hom · FAF 0.0052
| Admixed American205 / 35,430 | 0.00581 hom |
| Remaining individuals1 / 7,222 | 0.00014 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000142489; MAF= 0.01425%, 230/1614160 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00376529; MAF= 0.37653%, 226/60022 alleles, homozygotes = 2); grpmax FAF= 0.00336271.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000728337; MAF= 0.07283%, 206/282836 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.00578606; MAF= 0.57861%, 205/35430 alleles, homozygotes = 1); grpmax FAF= 0.00515383.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2. In addition, the PALB2 VCEP does not apply PP3 to missense variants. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply PP3 under the PALB2 missense rule. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via splicing (SpliceAI ≥ 0.2).
Evidence considered
- SpliceAI max delta score = 0.02.
- REVEL = 0.003.
- BayesDel = -0.705338.
- PALB2 VCEP PP3 instruction: missense do not use.
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the PALB2 BP4 splicing threshold of 0.1. However, the PALB2 VCEP does not apply BP4 to missense variants, so BP4 is not used here. REVEL is 0.003 and BayesDel is -0.705338, but these missense predictor results are not used to apply BP4 under the PALB2 missense rule. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via splicing (SpliceAI ≤ 0.1); do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.02.
- REVEL = 0.003.
- BayesDel = -0.705338.
- PALB2 VCEP BP4 instruction: missense do not use.
Sources
BP7 N/AThis is not a synonymous or deep intronic variant, and no RNA study showing a normal transcript was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based extensions require observed lack of aberrant RNA defect.
Evidence considered
- NM_024675.3:c.2027T>C is a missense exonic substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.003. BayesDel score = -0.705338.
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
230 / 1,614,160 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/142310/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23641448-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23630127-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.2027…
- OncoKB ↗www.oncokb.org/gene/PALB2/I676T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2027T%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= 0.000142489; MAF= 0.01425%, 230/1614160 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00376529; MAF= 0.37653%, 226/60022 alleles, homozygotes = 2); grpmax FAF= 0.00336271.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000728337; MAF= 0.07283%, 206/282836 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.00578606; MAF= 0.57861%, 205/35430 alleles, homozygotes = 1); grpmax FAF= 0.00515383.
ClinVar
This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign 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 = 0.02). REVEL score = 0.003. BayesDel score = -0.705338.
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.