About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.721A>G, p.(Asn241Asp)
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BP1Supporting
BP1 · supporting
This is a missense variant, and the PALB2 VCEP specification states BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2.
BS1Strong
BS1 · strong
PALB2 BS1 is met when gnomAD v4 grpmax filtering AF exceeds 0.01%. The workspace reports gnomAD v4 grpmax_faf 0.00602134, which is approximately 0.602%, far above the BS1 threshold.
BA1Stand alone
BA1 · stand alone
PALB2 BA1 is met when gnomAD v4 grpmax filtering AF exceeds 0.1%. The workspace reports grpmax_faf 0.00602134, which is approximately 0.602%, comfortably above the BA1 threshold.
Recorded classification: Benign
PALB2 Hereditary Breast, Ovarian and Pancreatic Cancer VCEP v1.2.0 qualitative ACMG/AMP classification
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.
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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 3 met · 7 not met · 5 not assessed · 13 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 VCEP specification defines BA1 at gnomAD v4 grpmax filtering AF >0.1%, BS1 at >0.01%, and BP1 for all missense variants.
In the assembled workspace, gnomAD v4 reports grpmax_faf 0.00602134 (~0.602%), which exceeds both the BA1 and BS1 PALB2 thresholds by a wide margin.
The variant is a missense substitution p.(Asn241Asp)/p.(N241D), so PALB2-specific BP1 also applies; ClinVar expert-panel benign classification is concordant but was not needed as an ACMG criterion because BA1 alone is sufficient for a benign call.
No criteria match.
Met · 3
BP1 SupportingThis is a missense variant, and the PALB2 VCEP specification states BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- NM_024675.4:c.721A>G = NP_078951.2:p.(Asn241Asp), a missense change.
- PALB2 BP1 rule: apply to all missense variants.
Sources
BS1 StrongPALB2 BS1 is met when gnomAD v4 grpmax filtering AF exceeds 0.01%. The workspace reports gnomAD v4 grpmax_faf 0.00602134, which is approximately 0.602%, far above the BS1 threshold. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.01% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 source_data.grpmax_faf = 0.006021340000000001 (~0.602%).
- PALB2 BS1 threshold: grpmax filtering AF >0.01% in gnomAD v4.
Sources
BA1 Stand alonePALB2 BA1 is met when gnomAD v4 grpmax filtering AF exceeds 0.1%. The workspace reports grpmax_faf 0.00602134, which is approximately 0.602%, comfortably above the BA1 threshold. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.1% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 source_data.grpmax_faf = 0.006021340000000001 (~0.602%).
- PALB2 BA1 threshold: grpmax filtering AF >0.1% in gnomAD v4.
Sources
Not met · 7 · evaluated, threshold not reached
PM2 PALB2 PM2_Supporting requires frequency ≤ 1/300,000 (0.000333%) in gnomAD v4. The workspace reports total AF 0.0003326799507361086, which is approximately 0.03327%, well above the PM2 threshold. Details ▾Hide ▴
Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
- gnomAD v4 total_af = 0.0003326799507361086 (~0.03327%).
- PALB2 PM2 threshold: ≤0.000333%.
Sources
PVS1 This is a missense substitution with no predicted splice impact (SpliceAI max delta 0.00), so PALB2 PVS1 does not apply. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree
Evidence considered
- Variant is missense p.(Asn241Asp), not a null variant.
- SpliceAI max delta score = 0.00.
Sources
BP7 BP7 is intended for synonymous/deep intronic variants or qualifying RNA evidence for silent/intronic variants; this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA lack-of-effect provisions are for silent/intronic variants.
Evidence considered
- Variant is missense p.(Asn241Asp).
Sources
BP4 Although SpliceAI predicts no splice impact (0.00), the PALB2 VCEP explicitly states BP4 should not be applied for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.00.
- PALB2 BP4: do not apply for missense variants.
Sources
PP3 SpliceAI does not predict splice impact (max delta 0.00), and the PALB2 VCEP also states PP3 should not be used for missense prediction itself. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score = 0.00.
- PALB2 PP3 missense: do not use; splicing threshold requires SpliceAI ≥0.2.
Sources
PM5 PALB2 PM5_Supporting is not to be used for missense changes; it is reserved for truncating/splice contexts described in the specification. Details ▾Hide ▴
Rule
Do not use for missense changes.
Evidence considered
- Variant is missense p.(Asn241Asp).
Sources
PS1 For PALB2, PS1 is not used for missense changes and instead only via the PALB2 splicing table where applicable; no splicing-based PS1 evidence exists here. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: see PALB2 PS1 table.
Evidence considered
- Variant is missense p.(Asn241Asp).
- SpliceAI max delta score = 0.00.
Sources
Not assessed · 5 · no assessment recorded
BS4 PALB2 BS4 is applicable, but no quantitative segregation or lack-of-segregation data were assembled in the workspace for this variant. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1; lower strengths for lesser negative segregation evidence.
Still missing
- No family segregation dataset or LOD/Bayes factor evidence in workspace.
Sources
PM3 PALB2 PM3 requires Fanconi anemia-style in trans evidence with scoring; no such case-level biallelic data were provided in the workspace. Details ▾Hide ▴
Rule
PM3 supporting/moderate/strong/very strong requires accumulation of PM3 points per PALB2 FA tables.
Still missing
- No phased in trans observations with a pathogenic PALB2 allele.
BS2 BS2 requires scored observations in healthy adults/co-occurrence framework per PALB2 FA tables; the workspace does not provide the necessary curated individual-level evidence. Details ▾Hide ▴
Rule
BS2 supporting/moderate/strong requires accumulation of BS2 points per PALB2 FA tables.
Still missing
- No qualifying healthy adult/co-occurrence observations with scoring.
PS4 PS4 requires a qualifying case-control result. The workspace does not provide a p-value plus odds ratio/hazard ratio/relative risk meeting PALB2 PS4 thresholds for this specific variant. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Still missing
- No qualifying variant-specific case-control statistics in workspace.
Sources
PP1 PP1 requires quantitative cosegregation or defined AR segregation counts. No such segregation analysis was present in the workspace. Details ▾Hide ▴
Rule
AD: LOD/Bayes factor thresholds; AR: segregation in affected relatives.
Still missing
- No family segregation evidence with LOD/Bayes factor.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/APALB2 PM4 is not applicable for this missense substitution; the specification limits PM4 to stop-loss variants. Details ▾Hide ▴
BP6 N/ABP6 is explicitly not for use by this VCEP. Details ▾Hide ▴
Sources
BP5 N/ABP5 is explicitly not applicable for PALB2 under this VCEP. Details ▾Hide ▴
Sources
BS3 N/ABS3 is marked not applicable in the PALB2 VCEP materials provided in this workspace. Details ▾Hide ▴
PP4 N/APP4 is not applicable for PALB2-related cancer predisposition in this VCEP framework. Details ▾Hide ▴
Sources
PM6 N/APM6 is not applicable for PALB2 under this VCEP. Details ▾Hide ▴
Sources
PM1 N/APM1 is not applicable in PALB2 because missense pathogenic variation is not yet confirmed as a disease mechanism under this specification. Details ▾Hide ▴
BP2 N/ABP2 is not applicable for PALB2 in this VCEP framework. Details ▾Hide ▴
Sources
PP2 N/APP2 is not applicable for PALB2 because missense is not an established disease mechanism in this specification. Details ▾Hide ▴
Sources
PS3 N/APS3 is marked not applicable in the PALB2 VCEP materials supplied in the workspace. Details ▾Hide ▴
BP3 N/ABP3 is not applicable for PALB2 under this VCEP. Details ▾Hide ▴
Sources
PP5 N/APP5 is explicitly not for use by this VCEP. Details ▾Hide ▴
Sources
PS2 N/APS2 is not applicable for PALB2 under this VCEP. Details ▾Hide ▴
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.721A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Asn241Asp)
- GRCh38
- chr16:23635825 T>C
- GRCh37
- chr16:23647146 T>C
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 |
|---|
Statements
No population statements were recorded.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 BP7 is intended for synonymous/deep intronic variants or qualifying RNA evidence for silent/intronic variants; this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA lack-of-effect provisions are for silent/intronic variants.
Evidence considered
- Variant is missense p.(Asn241Asp).
Sources
BP4 Although SpliceAI predicts no splice impact (0.00), the PALB2 VCEP explicitly states BP4 should not be applied for missense variants. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: no predicted impact via SpliceAI ≤0.1; do not apply for missense variants.
Evidence considered
- SpliceAI max delta score = 0.00.
- PALB2 BP4: do not apply for missense variants.
Sources
PP3 SpliceAI does not predict splice impact (max delta 0.00), and the PALB2 VCEP also states PP3 should not be used for missense prediction itself. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: predicted impact via SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score = 0.00.
- PALB2 PP3 missense: do not use; splicing threshold requires SpliceAI ≥0.2.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
Captured gnomAD v4.1 source record
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
Cancer hotspots
Captured Cancer Hotspots source record
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/126765/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647146-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635825-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.721A…
- OncoKB ↗www.oncokb.org/gene/PALB2/N241D
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
ClinVar
This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (8 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 = 0.00).
Functional
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104552978, n = 1 times).