About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.82T>A, p.(Tyr28Asn)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Per PALB2 VCEP v1.2.0, PM2 is applied at supporting strength when the variant frequency is ≤ 1/300,000 (0.000333%) in gnomAD v4. NM_024675.3:c.82T>A is absent from both gnomAD v2.1 and gnomAD v4.1, meeting the PM2_Supporting threshold.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
Per PALB2 VCEP v1.2.0, BP1 applies to all missense variants in PALB2 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. NM_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant and qualifies for BP1.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP1 supporting benign; 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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
3 reported laboratory submissions
3 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
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.
26 criteria with recorded statuses: 2 met · 6 not met · 0 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_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant in PALB2. It is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting per PALB2 VCEP v1.2.0 (allele frequency ≤ 0.000333%).
BP1_Supporting is applied as the PALB2 VCEP v1.2.0 assigns this criterion to all missense variants in PALB2, given that PALB2 has a low rate of functionally impactful missense variants and true pathogenic missense variants are thought to be exceedingly rare.
In silico predictors are not applied (PP3/BP4 not used for missense variants per VCEP). REVEL score is 0.219 and BayesDel score is 0.039. SpliceAI predicts no splice impact (max delta = 0.00).
This variant has been reported in ClinVar (ID 410148) as Uncertain Significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP and by 3 clinical laboratories. No case-control studies, co-segregation data, or functional studies specific to this variant were identified.
PVS1, PS1, PS3, PM1, PM5, PP2, PP3, PP4, PP5, BS3, BP2, BP4, BP5, BP6, and BP7 are not applicable per PALB2 VCEP v1.2.0 rules, predominantly because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. PS2, PS4, PM6, PP1, BA1, BS1, BS2, and BS4 are not met due to absence of qualifying evidence.
With PM2_Supporting (1 pathogenic supporting criterion) and BP1_Supporting (1 benign supporting criterion) in a VCEP framework with no other met criteria, the evidence is balanced between benign and pathogenic signals. The variant is classified as Uncertain Significance per the ACMG/AMP combining rules (Rule 31: ≥1 benign supporting + ≥1 pathogenic supporting → VUS with conflicting evidence). This is consistent with the ClinGen Expert Panel classification.
No criteria match.
Met · 2
PM2 SupportingPer PALB2 VCEP v1.2.0, PM2 is applied at supporting strength when the variant frequency is ≤ 1/300,000 (0.000333%) in gnomAD v4. NM_024675.3:c.82T>A is absent from both gnomAD v2.1 and gnomAD v4.1, meeting the PM2_Supporting threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 (0 alleles observed)
- Variant absent from gnomAD v4.1 (0 alleles observed)
- Meets PALB2 VCEP PM2_Supporting threshold of ≤ 0.000333%
Sources
BP1 SupportingPer PALB2 VCEP v1.2.0, BP1 applies to all missense variants in PALB2 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. NM_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant and qualifies for BP1. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 BP1 rule: 'Apply to all missense variants'
- Variant is a missense substitution: c.82T>A
- p.Tyr28Asn
- PALB2 has a low rate of functionally impactful missense variants
Sources
Not met · 6 · evaluated, threshold not reached
PS4 PS4 requires case-control studies demonstrating significantly increased prevalence in affected individuals versus controls (p ≤ 0.05 AND OR ≥ 3 or lower 95% CI ≥ 1.5). No case-control study reporting NM_024675.3:c.82T>A in affected versus unaffected individuals was identified. The variant is absent from gnomAD population databases and classified as Uncertain Significance by the ClinGen Expert Panel (ClinVar ID 410148), indicating insufficient case-level evidence to meet PS4 thresholds. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain Significance
- reviewed by expert panel
- Variant absent from gnomAD v2.1 and v4.1
- No published case-control study identified
Still missing
- No case-control study or proband counting data available for this specific variant
Sources
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members (AD: LOD ≥ 0.3 or LR ≥ 2:1 for supporting; AR: segregation in ≥ 1 affected relative). No published co-segregation data for NM_024675.3:c.82T>A were identified. Exploratory literature searches returned no family studies with this variant. Details ▾Hide ▴
Evidence considered
- No published segregation data identified for this variant
- Exploratory search for PALB2 Y28N segregation returned no results
Still missing
- No co-segregation or family study data available for this variant
Sources
BA1 BA1 requires a Grpmax Filtering AF > 0.1% in gnomAD v4. NM_024675.3:c.82T>A is absent from gnomAD v4.1 (0 alleles observed), far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v4.1
- PALB2 VCEP BA1 threshold: Grpmax Filtering AF > 0.1%
Sources
BS1 BS1 requires a Grpmax Filtering AF > 0.01% in gnomAD v4. NM_024675.3:c.82T>A is absent from gnomAD v4.1, which does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v4.1
- PALB2 VCEP BS1 threshold: Grpmax Filtering AF > 0.01%
Sources
BS2 BS2 (Fanconi Anemia BS2 tables) requires observation of the variant in a healthy adult individual for a recessive disorder expected to be fully penetrant at an early age, with points assigned per proband. No published report of NM_024675.3:c.82T>A in a healthy adult in a Fanconi anemia context was identified. Details ▾Hide ▴
Evidence considered
- No evidence of homozygous or compound heterozygous PALB2 c.82T>A in healthy adults identified
Still missing
- No BS2-qualifying clinical observations identified
Sources
BS4 BS4 requires quantitative co-segregation analysis demonstrating lack of segregation (LOD ≤ -0.32 for supporting, ≤ -0.64 for moderate, ≤ -1.28 for strong). No segregation or non-segregation data for NM_024675.3:c.82T>A were identified in the literature or databases. Details ▾Hide ▴
Evidence considered
- No published segregation or non-segregation data identified
Still missing
- No family-based co-segregation or lack-of-segregation data available
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice) or variants with a demonstrated splice defect per the PALB2 VCEP PVS1 Decision Tree. NM_024675.3:c.82T>A is a missense variant (p.Tyr28Asn) with no predicted splice impact (SpliceAI max delta score = 0.00), and therefore does not meet PVS1 eligibility criteria. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 PVS1 criteria require use of PALB2 PVS1 Decision Tree
- which is designed for null variants and splice-defect variants
- SpliceAI max delta score = 0.00 confirms no predicted splice impact
- Variant class is missense (c.82T>A
- p.Tyr28Asn)
- not a null variant
Sources
PS1 N/APer PALB2 VCEP v1.2.0, PS1 is not used for missense variants: 'Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 is only applied to splicing variants via the PALB2 PS1 Splicing table. NM_024675.3:c.82T>A is a missense variant with no splice impact (SpliceAI delta = 0.00). Details ▾Hide ▴
PS2 VCEPPS2 is marked not applicable by the PALB2 VCEP v1.2.0: informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease, and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
PS3 VCEPPS3 is marked not applicable by the PALB2 VCEP v1.2.0 for protein-level functional studies. The VCEP directs use of PVS1_O (RNA) for RNA-level splice defects only. Details ▾Hide ▴
PM1 VCEPPer PALB2 VCEP v1.2.0, PM1 is not applicable: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' Additionally, the variant does not lie in a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 PM1 rule: Not applicable for missense
- Cancer Hotspots: residue not significant
- exact variant not listed
Sources
PM5 N/APer PALB2 VCEP v1.2.0, PM5 is not used for missense changes: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with confirmed NMD-prone splicing impact. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 PM5 rule: Do not use for missense changes
- Variant is a missense substitution (p.Tyr28Asn)
Sources
PM6 VCEPPM6 is marked not applicable by the PALB2 VCEP v1.2.0: informative de novo occurrences have not yet been observed for autosomal dominant or autosomal recessive PALB2-related disease. Details ▾Hide ▴
PP2 VCEPPer PALB2 VCEP v1.2.0, PP2 is not applicable: 'Do not use: Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' Details ▾Hide ▴
PP3 N/APer PALB2 VCEP v1.2.0, PP3 is not used for missense variants. Published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. PP3 is only applied for splicing predictions when SpliceAI ≥ 0.2; NM_024675.3:c.82T>A has a SpliceAI max delta score of 0.00, which does not meet this threshold. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 PP3 rule: 'Missense: Do not use'
- SpliceAI max delta score = 0.00 (threshold for splicing PP3 is ≥ 0.2)
- REVEL score = 0.219 (not used per VCEP for missense)
- BayesDel score = 0.0388102 (not used per VCEP for missense)
Sources
PP4 VCEPPer PALB2 VCEP v1.2.0, PP4 is not applicable: breast cancer is a disease with multiple genetic etiologies (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For the AR condition (Fanconi anemia), PM3 is used instead for specific phenotype considerations. Details ▾Hide ▴
PP5 VCEPPer PALB2 VCEP v1.2.0, PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPBS3 is marked not applicable by the PALB2 VCEP v1.2.0. For protein-level functional studies showing no damaging effect, the VCEP directs use of alternative criteria. For RNA-level evidence of no splice defect, BP7(RNA) is used instead. Details ▾Hide ▴
BP2 VCEPPer PALB2 VCEP v1.2.0, BP2 is not applicable. The VCEP directs use of the ATM PM3/BP2 table, but this framework element is not applied to novel missense variants without co-occurrence data. Details ▾Hide ▴
BP4 N/APer PALB2 VCEP v1.2.0, BP4 is not used for missense variants: published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. BP4 is only applied for splicing predictions when SpliceAI ≤ 0.1; while NM_024675.3:c.82T>A has SpliceAI delta = 0.00, the VCEP explicitly states 'Missense: Do not use.' Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 BP4 rule: 'Missense: Do not use'
- SpliceAI max delta score = 0.00
- REVEL score = 0.219
- BayesDel score = 0.0388102 (not applied per VCEP for missense)
Sources
BP5 VCEPPer PALB2 VCEP v1.2.0, BP5 is not applicable. The VCEP states: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype. In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.' Details ▾Hide ▴
BP6 VCEPPer PALB2 VCEP v1.2.0, BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous variants and deep intronic variants per PALB2 VCEP v1.2.0. NM_024675.3:c.82T>A is a missense variant (p.Tyr28Asn), not a synonymous or deep intronic variant. BP7(RNA) requires observed lack of aberrant RNA defect, but no RNA studies for this variant have been identified. Details ▾Hide ▴
Evidence considered
- BP7 is designated for synonymous and deep intronic variants per VCEP
- Variant is missense
- not synonymous or deep intronic
Sources
PS5 N/APS5 is not a criterion in the PALB2 VCEP v1.2.0 framework and is not part of the standard ACMG/AMP 2015 criteria set used as a fallback. This criterion does not exist in the applicable classification framework. Details ▾Hide ▴
Evidence considered
- PS5 is absent from PALB2 VCEP v1.2.0 criteria and from ACMG/AMP 2015 standard criteria
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.82T>A
- Protein (HGVS p.)
- NP_078951.2:p.(Tyr28Asn)
- GRCh38
- chr16:23638096 A>T
- GRCh37
- chr16:23649417 A>T
- ClinVar
- 410148
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.219
- BayesDel
- 0.039
How the predictions were used
PP3 N/APer PALB2 VCEP v1.2.0, PP3 is not used for missense variants. Published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. PP3 is only applied for splicing predictions when SpliceAI ≥ 0.2; NM_024675.3:c.82T>A has a SpliceAI max delta score of 0.00, which does not meet this threshold. Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 PP3 rule: 'Missense: Do not use'
- SpliceAI max delta score = 0.00 (threshold for splicing PP3 is ≥ 0.2)
- REVEL score = 0.219 (not used per VCEP for missense)
- BayesDel score = 0.0388102 (not used per VCEP for missense)
Sources
BP4 N/APer PALB2 VCEP v1.2.0, BP4 is not used for missense variants: published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. BP4 is only applied for splicing predictions when SpliceAI ≤ 0.1; while NM_024675.3:c.82T>A has SpliceAI delta = 0.00, the VCEP explicitly states 'Missense: Do not use.' Details ▾Hide ▴
Evidence considered
- PALB2 VCEP v1.2.0 BP4 rule: 'Missense: Do not use'
- SpliceAI max delta score = 0.00
- REVEL score = 0.219
- BayesDel score = 0.0388102 (not applied per VCEP for missense)
Sources
BP7 N/ABP7 applies to synonymous variants and deep intronic variants per PALB2 VCEP v1.2.0. NM_024675.3:c.82T>A is a missense variant (p.Tyr28Asn), not a synonymous or deep intronic variant. BP7(RNA) requires observed lack of aberrant RNA defect, but no RNA studies for this variant have been identified. Details ▾Hide ▴
Evidence considered
- BP7 is designated for synonymous and deep intronic variants per VCEP
- Variant is missense
- not synonymous or deep intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.219. BayesDel score = 0.0388102.
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
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PMID 28319063 ↗Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.No paper-specific finding is recorded.
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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.
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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.
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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.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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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 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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 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/410148/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23649417-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23638096-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.82T%…
- OncoKB ↗www.oncokb.org/gene/PALB2/Y28N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.82T%3EA
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 410148)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.219. BayesDel score = 0.0388102.
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.