About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.514_517del, p.(Ser172GlyfsTer4)
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 frameshift deletion, NM_024675.3:c.514_517del, predicted to cause p.(Ser172GlyfsTer4) [p.(S172Gfs*4)], creating a premature stop codon very early in PALB2. The PALB2 specification recognizes loss of function as an established disease mechanism and directs use of the PALB2 PVS1 decision tree for null variants; the available evidence supports full-strength PVS1 for this early truncating event.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. The observed population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).
PM5Supporting
PM5 · supporting
This variant is a truncating frameshift with a premature termination codon at p.(S172Gfs*4), which is far upstream of the PALB2 PM5 cutoff at p.Tyr1183*. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5_Supporting.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 · 7 not met · 5 not assessed · 12 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 NM_024675.3:c.514_517del (NP_078951.2:p.(Ser172GlyfsTer4); p.(S172Gfs*4)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including expert panel review.
This variant is absent from gnomAD v4.1 and gnomAD v2.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 thresholds.
This deletion causes an early frameshift with a premature stop codon, and the PALB2 disease-specific framework supports loss-of-function interpretation for this null variant with PVS1_VeryStrong and PM5_Supporting for a truncating variant upstream of p.Tyr1183.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), so PP3 is not met and the interpretation is driven by the truncating effect rather than an added predicted splice defect.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a frameshift deletion, NM_024675.3:c.514_517del, predicted to cause p.(Ser172GlyfsTer4) [p.(S172Gfs*4)], creating a premature stop codon very early in PALB2. The PALB2 specification recognizes loss of function as an established disease mechanism and directs use of the PALB2 PVS1 decision tree for null variants; the available evidence supports full-strength PVS1 for this early truncating event. Details ▾Hide ▴
Rule
Use PALB2 PVS1 decision tree for null variants.
Evidence considered
- Variant consequence: frameshift with premature stop at p.(S172Gfs*4).
- PALB2 loss of function is an established disease mechanism in the CSPEC/VCEP framework.
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. The observed population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). Details ▾Hide ▴
Rule
Use as PM2_Supporting when frequency is ≤1/300,000 (0.000333%) in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1.
- Absent from gnomAD v2.1.
Sources
PM5 SupportingThis variant is a truncating frameshift with a premature termination codon at p.(S172Gfs*4), which is far upstream of the PALB2 PM5 cutoff at p.Tyr1183*. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5_Supporting. Details ▾Hide ▴
Rule
Apply PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.
Evidence considered
- Variant consequence: p.(S172Gfs*4).
- PALB2 PM5 uses a truncation-cutoff rule rather than same-residue missense logic.
Sources
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PS1 This variant is a frameshift deletion, not a missense change, and no PALB2 PS1 splice-table evidence was identified for this variant. PS1 is not met. Details ▾Hide ▴
Rule
Missense PS1 is not used for PALB2; splicing PS1 requires the PALB2 PS1 table.
Evidence considered
- PALB2 PS1 is limited to defined splicing-table scenarios and not to truncating frameshift variants.
Still missing
- No qualifying PALB2 PS1 splice comparator evidence was identified.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the PALB2 PP3 splice threshold of 0.2. In addition, the PALB2 specification does not use missense computational predictors for this context. PP3 is therefore not met. Details ▾Hide ▴
Rule
Splicing PP3 requires predicted splice impact via SpliceAI ≥0.2; missense PP3 is not used for PALB2.
Evidence considered
- SpliceAI max delta score = 0.00.
Sources
BA1 This variant is absent from gnomAD v4.1, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering allele frequency >0.1% in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v4.1.
- Absent from gnomAD v2.1.
Sources
BS1 This variant is absent from gnomAD v4.1, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax filtering allele frequency >0.01% in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v4.1.
- Absent from gnomAD v2.1.
Sources
BP1 This variant is a frameshift deletion, not a missense variant, so it does not meet the PALB2 BP1 rule that is applied to missense variants. Details ▾Hide ▴
Rule
Apply to all missense variants.
Evidence considered
- Variant consequence: frameshift
- p.(Ser172GlyfsTer4).
- PALB2 BP1 applies to missense variants.
Sources
cspec ↗pvs1_variant_assessment
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of 0.1), but the variant still causes an early frameshift with a premature stop codon. Available computational evidence therefore does not support a no-impact interpretation for the gene product, and BP4 is not met. Details ▾Hide ▴
Rule
Splicing BP4 requires no predicted splice impact via SpliceAI ≤0.1; missense BP4 is not used for PALB2.
Evidence considered
- SpliceAI max delta score = 0.00.
- Variant consequence: frameshift with premature stop.
Sources
BP7 This variant is a coding frameshift deletion rather than a synonymous or deep intronic variant, so BP7 is not met. Details ▾Hide ▴
Rule
BP7 applies to synonymous and defined deep intronic variants, or RNA evidence showing no aberrant splicing for those variant classes.
Evidence considered
- Variant consequence: frameshift
- not synonymous or deep intronic.
Sources
cspec ↗pvs1_variant_assessment
Not assessed · 5 · no assessment recorded
PS4 Although PM2_Supporting is met because the variant is absent from gnomAD, no case-control study or exact-variant prevalence data were identified showing a statistically significant enrichment in affected individuals, so PS4 cannot be assessed. Details ▾Hide ▴
Rule
Case-control studies with p≤0.05 and OR/HR/RR ≥3 or lower 95% CI ≥1.5.
Evidence considered
- Absent from gnomAD v4.1.
- ClinVar contains pathogenic submissions and expert panel review
- but no case-control statistics were identified here.
Still missing
- Exact-variant case-control data with p-value and odds ratio or relative risk were not identified.
Sources
PM3 No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Use Fanconi anemia PM3 point system; PM3_Supporting at 1 point, PM3 at 2 points, PM3_Strong at 4 points, PM3_VeryStrong at 8 points.
Evidence considered
- PALB2 PM3 uses Fanconi anemia point-based in-trans evidence.
Still missing
- Phase-confirmed biallelic case data for Fanconi anemia were not identified.
Sources
PP1 No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AD: LOD ≥0.3 / 0.6 / 1.26 or Bayes factor ≥2:1 / 4:1 / 18:1 for Supporting / Moderate / Strong.
Evidence considered
- PALB2 PP1 requires quantitative segregation evidence.
Still missing
- Family segregation data with quantitative evidence were not identified.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals or providing the Fanconi anemia point-based observations required for BS2, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Use Fanconi anemia BS2 point system; BS2_Supporting at 1 point, BS2_Moderate at 2 points, BS2 at 4 points.
Evidence considered
- PALB2 BS2 requires specific unaffected or co-occurrence evidence and does not use population databases such as gnomAD.
Still missing
- Unaffected carrier data or qualifying BS2 point-based evidence were not identified.
Sources
BS4 No quantitative non-segregation data, unaffected carrier data, or Bayes factor/LOD evidence were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
LOD ≤ -1.28 or Bayes Factor ≤0.053:1 for BS4_Strong; lower thresholds for BS4_Moderate or BS4_Supporting.
Evidence considered
- PALB2 BS4 requires quantitative non-segregation evidence.
Still missing
- Family-level non-segregation data with quantitative LOD or Bayes factor assessment were not identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not used by the PALB2 specification. 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 by this PALB2 specification for protein functional evidence, and no separate RNA-based rule applicable to this variant was identified that would replace the null-variant framework already captured by PVS1. Details ▾Hide ▴
Rule
Not applicable for PALB2 protein functional evidence; RNA damaging evidence is handled under PVS1_O per specification.
Evidence considered
- PALB2 VCEP marks PS3 as not applicable.
Sources
PM1 N/APM1 is not used for PALB2 because missense pathogenic variation in defined hotspot or critical-domain settings is not an established disease mechanism in this framework. Details ▾Hide ▴
PM4 N/AThe PALB2 specification does not use PM4 for this type of variant; PM4 is reserved for stop-loss variants and not for this frameshift deletion. Details ▾Hide ▴
Rule
Do not use for in-frame insertions/deletions less than a single exon; use for stop-loss variants only.
Evidence considered
- PALB2 PM4 is not applicable except for stop-loss variants.
Sources
PM6 N/APM6 is not used by the PALB2 specification. 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 mechanism of disease in this framework. Details ▾Hide ▴
PP4 N/APP4 is not used by the PALB2 specification for the autosomal dominant hereditary cancer presentation relevant here. Details ▾Hide ▴
Rule
Do not use for AD disorder; for AR disorder use PM3 for phenotype considerations.
Evidence considered
- PALB2 VCEP marks PP4 as not applicable.
Sources
BS3 N/ABS3 is not used by this PALB2 specification for protein functional evidence, and no RNA-based benign evidence framework applicable to this variant was identified. Details ▾Hide ▴
Rule
Not applicable for PALB2 protein functional evidence; RNA lack-of-effect is handled under BP7_O per specification.
Evidence considered
- PALB2 VCEP marks BS3 as not applicable.
Sources
BP2 N/ABP2 is not used by the PALB2 specification. Details ▾Hide ▴
Rule
Not applicable for PALB2.
Evidence considered
- PALB2 VCEP marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used for PALB2. Details ▾Hide ▴
BP5 N/ABP5 is not used by the PALB2 specification because additional molecular findings do not reliably exclude a contribution from PALB2-related cancer predisposition. Details ▾Hide ▴
Rule
Do not use BP5 for PALB2.
Evidence considered
- PALB2 VCEP marks BP5 as not applicable.
Sources
BP6 N/ABP6 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 BP6 as not for use.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.3
- Coding (HGVS c.)
- NM_024675.3:c.514_517del
- Protein (HGVS p.)
- NP_078951.2:p.(Ser172GlyfsTer4)
- GRCh38
- chr16:23636028 CCAGA>C
- GRCh37
- chr16:23647349 CCAGA>C
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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
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 0.00), which is below the PALB2 PP3 splice threshold of 0.2. In addition, the PALB2 specification does not use missense computational predictors for this context. PP3 is therefore not met. Details ▾Hide ▴
Rule
Splicing PP3 requires predicted splice impact via SpliceAI ≥0.2; missense PP3 is not used for PALB2.
Evidence considered
- SpliceAI max delta score = 0.00.
Sources
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of 0.1), but the variant still causes an early frameshift with a premature stop codon. Available computational evidence therefore does not support a no-impact interpretation for the gene product, and BP4 is not met. Details ▾Hide ▴
Rule
Splicing BP4 requires no predicted splice impact via SpliceAI ≤0.1; missense BP4 is not used for PALB2.
Evidence considered
- SpliceAI max delta score = 0.00.
- Variant consequence: frameshift with premature stop.
Sources
BP7 This variant is a coding frameshift deletion rather than a synonymous or deep intronic variant, so BP7 is not met. Details ▾Hide ▴
Rule
BP7 applies to synonymous and defined deep intronic variants, or RNA evidence showing no aberrant splicing for those variant classes.
Evidence considered
- Variant consequence: frameshift
- not synonymous or deep intronic.
Sources
cspec ↗pvs1_variant_assessment
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
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/461007/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647349-CCAGA-C?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23636028-CCAGA-C?datase…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.3%3Ac.514_…
- OncoKB ↗www.oncokb.org/gene/PALB2/S172Gfs*4
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.514_517del
- 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 Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 461007)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.