About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.682C>T, p.(Gln228Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change predicted to introduce a premature stop codon early in PALB2. PALB2 loss of function is an established disease mechanism in the PALB2 specification, and the available evidence supports applying PVS1 at very strong strength for this truncating variant. SpliceAI shows no significant alternate splice effect prediction (max delta score 0.01), so there is no computational evidence suggesting a different primary mechanism.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.
PM5Supporting
PM5 · supporting
The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This variant introduces p.Gln228Ter, which is upstream of p.Tyr1183, so PM5_Supporting is met.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM2 supporting, PVS1 very strong, PP5 supporting, PM5 supporting; maps to Pathogenic.
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
1 / 1,614,016 alleles
gnomAD v4.1: 1 / 1,614,016 alleles. Recorded AF 6.19573e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 · 4 not met · 5 not assessed · 15 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.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.
This variant introduces a premature stop codon early in PALB2, and published PALB2 studies together with the PALB2 specification support loss of function as an established disease mechanism for hereditary cancer predisposition.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which does not support PP3 and is consistent with the primary consequence being protein truncation rather than altered splicing.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a nonsense change predicted to introduce a premature stop codon early in PALB2. PALB2 loss of function is an established disease mechanism in the PALB2 specification, and the available evidence supports applying PVS1 at very strong strength for this truncating variant. SpliceAI shows no significant alternate splice effect prediction (max delta score 0.01), so there is no computational evidence suggesting a different primary mechanism. Details ▾Hide ▴
Rule
Use PALB2 PVS1 Decision Tree.
Evidence considered
- Variant bucket: nonsense
- PALB2 LoF mechanism supported in the gene-level PVS1 context
- PVS1 variant scaffold suggests default PVS1
- SpliceAI max delta score 0.01
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗PMID:17200671 ↗PMID:25099575 ↗PMID:28779002 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met. Details ▾Hide ▴
Rule
Use as PM2_Supporting when frequency is ≤1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.19573e-07 (0.00006%)
- AC 1/AN 1
- 614
- 016
- PALB2 PM2_Supporting threshold ≤0.000333%
Sources
PM5 SupportingThe PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This variant introduces p.Gln228Ter, which is upstream of p.Tyr1183, so PM5_Supporting is met. Details ▾Hide ▴
Rule
Apply as PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.
Evidence considered
- Protein consequence p.Gln228Ter (p.Q228*)
- PALB2 PM5_Supporting rule for truncating variants upstream of p.Tyr1183
Sources
cspec ↗pvs1_variant_assessment
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of 0.2. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but PALB2 PP3 is not applied to this truncating variant on the basis of missense-oriented predictors. Details ▾Hide ▴
Rule
Splicing: predicted impact via splicing only when SpliceAI ≥0.2; missense PP3 is not used.
Evidence considered
- SpliceAI max delta score 0.01
- BayesDel score 0.63
- REVEL unavailable
- HCI prior not available for PALB2
Sources
BA1 The highest observed gnomAD v4.1 population frequency is 0.00008%, which is far 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 v4.1 best subpopulation AF 8.47448e-07 (0.00008%)
- PALB2 BA1 threshold >0.1%
Sources
BS1 The highest observed gnomAD v4.1 population frequency is 0.00008% (1/1,180,014 alleles in European non-Finnish), 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 v4.1 best subpopulation AF 8.47448e-07 (0.00008%)
- PALB2 BS1 threshold >0.01%
Sources
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 BP4 splice threshold of 0.1. However, this variant still creates a premature termination codon, so the lack of predicted splice disruption does not provide benign evidence against the truncating effect. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but these do not establish a benign interpretation for this nonsense variant. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01
- BayesDel score 0.63
- REVEL unavailable
- HCI prior not available for PALB2
Sources
Not assessed · 5 · no assessment recorded
PS4 Published studies support increased cancer risk for truncating PALB2 variants as a class, but no exact variant-specific case-control dataset with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 was identified for this variant, so PS4 cannot be applied. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- PALB2 PS4 requires case-control evidence with p-value ≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5
- Available publications support truncating PALB2 variants as a class rather than this exact variant
Still missing
- Exact variant-specific case-control data
- Variant-specific effect estimate and confidence interval meeting the PALB2 PS4 threshold
Sources
PM3 No biallelic Fanconi anemia case data or confirmed in trans observations with another pathogenic PALB2 variant were identified for this variant, so PM3 cannot be scored. Details ▾Hide ▴
Rule
PM3 scoring for Fanconi anemia requires point-based evidence from probands with variants in trans.
Evidence considered
- PALB2 PM3 uses Fanconi anemia point-based scoring
- No qualifying in trans or biallelic case data were identified for this variant
Still missing
- Confirmed phase with another pathogenic PALB2 variant
- Fanconi anemia proband-level evidence for point assignment
Sources
PP1 No family cosegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 / 0.6 / 1.26 or LR ≥2:1 / 4:1 / 18:1 for supporting/moderate/strong.
Evidence considered
- PALB2 PP1 requires quantitative cosegregation evidence
- No family segregation dataset was identified for this variant
Still missing
- Quantitative segregation data in affected relatives
- LOD score or Bayes factor calculated under the PALB2 specification
Sources
BS2 No qualifying observations were identified in healthy adults that would allow point-based BS2 assessment for this variant. The single gnomAD observation does not satisfy PALB2 BS2 because population cohorts are not used for this rule. Details ▾Hide ▴
Rule
BS2 requires point-based evidence from qualifying unaffected individuals; do not use population-based cohorts such as gnomAD.
Evidence considered
- PALB2 BS2 excludes use of population-based cohorts such as gnomAD
- gnomAD v4.1 shows 1 allele and 0 homozygotes
Still missing
- Clinically evaluated unaffected adult carriers meeting PALB2 BS2 requirements
- Point-based BS2 evidence under the Fanconi anemia tables
Sources
BS4 No family-based nonsegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1 for BS4_Strong; lower thresholds for moderate/supporting.
Evidence considered
- PALB2 BS4 requires quantitative nonsegregation evidence
- No family nonsegregation dataset was identified for this variant
Still missing
- Quantitative nonsegregation data for affected and unaffected relatives
- LOD score or Bayes factor calculated under the PALB2 specification
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APALB2 PS1 is reserved for specific splice-table scenarios and is not used for this nonsense variant. Details ▾Hide ▴
Rule
Missense: do not use. Splicing: see PALB2 PS1 table.
Evidence considered
- Variant bucket: nonsense
- PALB2 PS1 instructions direct use to the splicing table rather than truncating variants
Sources
cspec ↗pvs1_variant_assessment
PS2 N/APS2 is not used for PALB2 in this specification. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 PS2 is designated not applicable
Sources
PS3 N/APS3 is not used for PALB2 in this specification for the present variant context. Details ▾Hide ▴
Rule
Not applicable in this PALB2 specification.
Evidence considered
- PALB2 PS3 is listed as not applicable
Sources
PM1 N/APM1 is not used for PALB2 because missense pathogenic variation in defined hotspot domains is not an established disease mechanism for this specification. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 PM1 is designated not applicable
- No hotspot-based PALB2 rule applies here
Sources
PM4 N/AThis variant is a nonsense substitution, not a stop-loss variant, and PALB2 does not use PM4 for this variant type. 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
- Variant bucket: nonsense
- PALB2 PM4 is reserved for stop-loss variants
Sources
cspec ↗pvs1_variant_assessment
PM6 N/APM6 is not used for PALB2 in this specification. Details ▾Hide ▴
Rule
Do not use for AD or AR disease.
Evidence considered
- PALB2 PM6 is designated not applicable
Sources
PP2 N/APP2 is not used for PALB2 because missense variation is not an established disease mechanism in this specification, and this variant is not missense. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 PP2 is designated not applicable
- Variant bucket: nonsense
Sources
cspec ↗pvs1_variant_assessment
PP4 N/APP4 is not used for PALB2-related autosomal dominant cancer predisposition because the phenotype is not sufficiently specific for a single genetic cause. Details ▾Hide ▴
Rule
Do not use for AD disorder; for AR disorder use PM3 for specific phenotype considerations.
Evidence considered
- PALB2 PP4 is designated not applicable for the autosomal dominant condition
Sources
BS3 N/ABS3 is not used for PALB2 in this specification for the present variant context. Details ▾Hide ▴
Rule
Not applicable in this PALB2 specification.
Evidence considered
- PALB2 BS3 is listed as not applicable
Sources
BP1 N/ABP1 applies to missense variants. This variant is a nonsense change and does not meet the PALB2 BP1 use case. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- Variant bucket: nonsense
- PALB2 BP1 applies to missense variants
Sources
cspec ↗pvs1_variant_assessment
BP2 N/ABP2 is not used in the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable in this PALB2 specification.
Evidence considered
- PALB2 BP2 is designated not applicable
Sources
BP3 N/ABP3 is not used for PALB2 because this specification does not recognize a qualifying repetitive benign region for this gene, and this variant is not an in-frame indel. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 BP3 is designated not applicable
- Variant bucket: nonsense
Sources
cspec ↗pvs1_variant_assessment
BP5 N/ABP5 is not used for PALB2 because co-occurring pathogenic variants do not reliably exclude a contribution from PALB2-related cancer predisposition. Details ▾Hide ▴
Rule
Do not use for PALB2.
Evidence considered
- PALB2 BP5 is designated not applicable by the specification
Sources
BP6 N/ABP6 is not used by this PALB2 specification. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PALB2 BP6 is not applicable for this VCEP
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants and does not apply to this nonsense coding change. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, with optional RNA-based weighting.
Evidence considered
- Variant bucket: nonsense
- PALB2 BP7 applies to synonymous and deep intronic variants
Sources
cspec ↗pvs1_variant_assessment
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.682C>T
- Protein (HGVS p.)
- NP_078951.2:p.(Gln228Ter)
- GRCh38
- chr16:23635864 G>A
- GRCh37
- chr16:23647185 G>A
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
1 / 1,614,016 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,016 alleles · 0 hom
| European (non-Finnish)1 / 1,180,014 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19573e-07; MAF= 0.00006%, 1/1614016 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of 0.2. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but PALB2 PP3 is not applied to this truncating variant on the basis of missense-oriented predictors. Details ▾Hide ▴
Rule
Splicing: predicted impact via splicing only when SpliceAI ≥0.2; missense PP3 is not used.
Evidence considered
- SpliceAI max delta score 0.01
- BayesDel score 0.63
- REVEL unavailable
- HCI prior not available for PALB2
Sources
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 BP4 splice threshold of 0.1. However, this variant still creates a premature termination codon, so the lack of predicted splice disruption does not provide benign evidence against the truncating effect. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but these do not establish a benign interpretation for this nonsense variant. Details ▾Hide ▴
Rule
Splicing: no predicted impact via splicing (SpliceAI ≤0.1). Do not apply for missense variants.
Evidence considered
- SpliceAI max delta score 0.01
- BayesDel score 0.63
- REVEL unavailable
- HCI prior not available for PALB2
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants and does not apply to this nonsense coding change. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, with optional RNA-based weighting.
Evidence considered
- Variant bucket: nonsense
- PALB2 BP7 applies to synonymous and deep intronic variants
Sources
cspec ↗pvs1_variant_assessment
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.63.
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
1 / 1,614,016 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/484222/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647185-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635864-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.682C…
- OncoKB ↗www.oncokb.org/gene/PALB2/Q228*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107875955
- 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= 6.19573e-07; MAF= 0.00006%, 1/1614016 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic 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 = 0.01). BayesDel score = 0.63.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55168872, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.