About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.2580G>T, p.(Glu860Asp)
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
Variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes). Meets VCEP PM2_Supporting threshold (frequency ≤ 0.000333% in gnomAD v4).
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
VCEP PALB2 specification: BP1 applies to all missense variants at supporting benign strength. PALB2 has a low rate of missense variants that are non-functional in relevant assays, and true missense pathogenic variants are thought to be exceedingly rare.
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 benign; 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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
5 reported laboratory submissions
4 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.
27 criteria with recorded statuses: 2 met · 2 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
NM_024675.4:c.2580G>T (p.Glu860Asp) is a missense variant in PALB2, a gene where loss of function is an established mechanism of disease but missense pathogenicity is not yet confirmed.
The variant is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (frequency ≤ 0.000333%).
Per VCEP PALB2 specification, BP1_Supporting is applied to all missense variants given the very low likelihood that missense variants in PALB2 are pathogenic.
Multiple VCEP criteria are not applicable to missense variants in PALB2: PVS1, PS1, PM1, PM5, PP2, PP3, BP4. Additional criteria (PS3, BS3, PS2, PM6, PP4, PP5, BP2, BP5, BP6) are not applicable per VCEP specification.
SpliceAI predicts no splice impact (max delta 0.01). REVEL score (0.021) and BayesDel score (-0.521846) are consistent with a benign computational prediction for the missense change, though not formally applied as criteria per VCEP rules.
ClinVar reports this variant as Uncertain significance (4 clinical laboratories) and Likely benign (1 clinical laboratory). No expert panel classification is available.
With PM2_Supporting (1 pathogenic supporting point) and BP1_Supporting (1 benign supporting point), the variant falls into the Uncertain Significance category per ACMG/AMP 2015 combination rules (Rule 31: conflicting supporting evidence).
No criteria match.
Met · 2
PM2 SupportingVariant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes). Meets VCEP PM2_Supporting threshold (frequency ≤ 0.000333% in gnomAD v4). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- absent from gnomAD v4.1
- frequency 0% ≤ 0.000333% VCEP threshold.
Sources
BP1 SupportingVCEP PALB2 specification: BP1 applies to all missense variants at supporting benign strength. PALB2 has a low rate of missense variants that are non-functional in relevant assays, and true missense pathogenic variants are thought to be exceedingly rare. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Apply to all missense variants.' NM_024675.4:c.2580G>T is a missense variant (p.Glu860Asp).
Sources
Not met · 2 · evaluated, threshold not reached
BA1 Variant is absent from gnomAD v4.1. Does not meet the VCEP BA1 threshold (Grpmax Filtering AF >0.1% in gnomAD v4). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- AF 0% does not exceed BA1 threshold of >0.1%.
Sources
BS1 Variant is absent from gnomAD v4.1. Does not meet the VCEP BS1 threshold (Grpmax Filtering AF >0.01% in gnomAD v4). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- AF 0% does not exceed BS1 threshold of >0.01%.
Sources
Not assessed · 5 · no assessment recorded
PS4 VCEP requires case-control studies with p≤0.05 AND (OR≥3 OR lower 95% CI ≥1.5). No case-control study meeting this threshold has been identified for this variant. ClinVar reports 5 clinical laboratory submissions (4 VUS, 1 likely benign) but no case-control data. Details ▾Hide ▴
PP1 No co-segregation data available for this variant. VCEP requires quantitative co-segregation analysis (LOD scores or Bayes Factors for AD condition) or affected relative counts for AR condition. Details ▾Hide ▴
Evidence considered
- No segregation data identified for NM_024675.4:c.2580G>T.
Still missing
- No co-segregation data available to meet VCEP PP1 thresholds.
Sources
BS2 VCEP BS2 requires Fanconi Anemia proband points from BS2 tables. No Fanconi Anemia proband data available for this variant. Details ▾Hide ▴
Evidence considered
- No Fanconi Anemia proband data available to assign BS2 points.
Still missing
- No Fanconi Anemia proband data for BS2 point assignment.
Sources
BS4 VCEP BS4 requires quantitative co-segregation analysis (LOD scores or Bayes Factors). No segregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available to meet VCEP BS4 quantitative thresholds.
Still missing
- No co-segregation data for BS4 LOD/Bayes Factor calculation.
Sources
PS5 No pathogenic missense variant has been established at codon Glu860 in PALB2. Insufficient evidence to apply PS5 (same amino acid change as established pathogenic variant). Details ▾Hide ▴
Evidence considered
- No ClinVar expert-panel pathogenic or likely pathogenic missense variant identified at Glu860.
Still missing
- No established pathogenic missense at Glu860 for PS5 comparison.
Sources
pm5_candidates
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Glu860Asp); does not meet PVS1 null-variant criteria (nonsense, frameshift, canonical splice ±1,2). PALB2 PVS1 Decision Tree applies to null variants, not missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant in PALB2
- variant bucket 'other' per PVS1 assessment
- no null-variant mechanism.
Sources
pvs1_variant_assessmentcspec ↗
PS1 N/AVCEP PALB2 specification: PS1 is not used for missense variants. Missense changes are not yet confirmed as a mechanism of disease for PALB2. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.'
Sources
PS2 VCEPVCEP PALB2 specification: PS2 is not applicable. Informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease. Details ▾Hide ▴
PS3 VCEPVCEP PALB2 specification: PS3 is not applicable for protein-level functional studies. Color Health submission notes 'functional studies have not been performed for this variant.' Details ▾Hide ▴
PM1 VCEPVCEP PALB2 specification: PM1 is not applicable. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.'
Sources
PM5 N/AVCEP PALB2 specification: PM5 is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with NMD-prone PTCs. Not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 candidate search confirmed not applicable.
Sources
PM6 VCEPVCEP PALB2 specification: PM6 is not applicable. Informative de novo occurrences have not yet been observed for PALB2-related disease. Details ▾Hide ▴
PP2 VCEPVCEP PALB2 specification: PP2 is not applicable. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'
Sources
PP3 N/AVCEP PALB2 specification: PP3 is not used for missense variants. PP3 applies only to splicing predictions (SpliceAI ≥0.2). SpliceAI max delta score is 0.01, which does not meet the splicing threshold. REVEL score 0.021 and BayesDel score -0.521846 are consistent with a benign computational prediction but are not applied under VCEP rules. Details ▾Hide ▴
Evidence considered
- VCEP rule: PP3 not for missense
- SpliceAI max delta 0.01 < 0.2
- REVEL 0.021
- BayesDel -0.521846.
Sources
PP4 VCEPVCEP PALB2 specification: PP4 is not applicable. Breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes. Details ▾Hide ▴
PP5 VCEPVCEP PALB2 specification: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPVCEP PALB2 specification: BS3 is not applicable for protein-level functional studies. No variant-specific benign functional evidence identified. Details ▾Hide ▴
Evidence considered
- VCEP rule: BS3 not applicable for PALB2 missense functional studies.
Sources
BP2 VCEPVCEP PALB2 specification: BP2 is not applicable. Uses ATM PM3/BP2 table; not relevant for PALB2. Details ▾Hide ▴
BP3 VCEPSkipped per case directive; substitution variant, not an in-frame deletion/insertion. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 applies to in-frame deletions/insertions in repetitive regions.
BP4 N/AVCEP PALB2 specification: BP4 is not used for missense variants. Published predictors have yet to achieve reliable functional outcome prediction for PALB2 missense variants. SpliceAI max delta 0.01 is ≤0.1 but BP4 is explicitly not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Missense: Do not use.' SpliceAI max delta 0.01 indicates no predicted splice impact.
Sources
BP5 VCEPVCEP PALB2 specification: BP5 is not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance. Details ▾Hide ▴
BP6 VCEPVCEP PALB2 specification: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 is restricted to synonymous and deep intronic variants beyond +7 (donor) and -21 (acceptor). NM_024675.4:c.2580G>T is a missense variant in exon 6; BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant in coding exon
- BP7 applies only to synonymous and deep intronic variants.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.2580G>T
- Protein (HGVS p.)
- NP_078951.2:p.(Glu860Asp)
- GRCh38
- chr16:23629210 C>A
- GRCh37
- chr16:23640531 C>A
- ClinVar
- 484223
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.021
- BayesDel
- -0.522
How the predictions were used
PP3 N/AVCEP PALB2 specification: PP3 is not used for missense variants. PP3 applies only to splicing predictions (SpliceAI ≥0.2). SpliceAI max delta score is 0.01, which does not meet the splicing threshold. REVEL score 0.021 and BayesDel score -0.521846 are consistent with a benign computational prediction but are not applied under VCEP rules. Details ▾Hide ▴
Evidence considered
- VCEP rule: PP3 not for missense
- SpliceAI max delta 0.01 < 0.2
- REVEL 0.021
- BayesDel -0.521846.
Sources
BP4 N/AVCEP PALB2 specification: BP4 is not used for missense variants. Published predictors have yet to achieve reliable functional outcome prediction for PALB2 missense variants. SpliceAI max delta 0.01 is ≤0.1 but BP4 is explicitly not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- VCEP rule: 'Missense: Do not use.' SpliceAI max delta 0.01 indicates no predicted splice impact.
Sources
BP7 N/ABP7 is restricted to synonymous and deep intronic variants beyond +7 (donor) and -21 (acceptor). NM_024675.4:c.2580G>T is a missense variant in exon 6; BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant in coding exon
- BP7 applies only to 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 = 0.021. BayesDel score = -0.521846.
7 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 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. General practice guideline for BRCA-related cancer.Does not name this variant
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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.2014Summaries for patients: assessing the genetic risk for BRCA-related breast or ovarian cancer in women. Patient-level summary of USPSTF recommendations.Does not name this variant
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PMID 24432435 ↗PMID 24432435Nelson HD et al. · 2013No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint coStandards and guidelines for the interpretation of sequence variants — a joint consensus recommendation of ACMG and AMP. Provides the generic ACMG/AMP classification framework used as reference.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteSherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Describes a systematic refinement of variant classification rules.Does not name this variant
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PMID 31429903 ↗Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related CancerRisk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement.Does not name this variant
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PMID 31479213 ↗PMID 31479213No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
4 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/484223/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23640531-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23629210-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-23629210-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.2580…
- OncoKB ↗www.oncokb.org/gene/PALB2/E860D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.2580G%3ET
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 484223)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.021. BayesDel score = -0.521846.
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.