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PALB2c.2052delLikely pathogenic
Print report
Variant interpretation report

PALB2 c.2052del, p.(Arg686GlyfsTer23)

NM_024675.4:c.2052del NP_078951.2:p.(Arg686GlyfsTer23) Frameshift · exon 5 View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PALB2

PALB2 encodes a tumor suppressor protein that partners with BRCA2 (and also interacts with BRCA1) to repair double-stranded DNA breaks through the homologous recombination pathway. It acts as a scaffold that stabilizes BRCA2 in the cell nucleus and helps recruit DNA-repair machinery to sites of damage. Inherited mutations in PALB2 increase susceptibility to breast cancer, with smaller associated risks for ovarian, pancreatic, and prostate cancer and melanoma, and inheriting two mutated copies causes Fanconi anemia complementation group N. Rare somatic alterations in PALB2 are also found across various tumor types.

NCBI Gene ↗ OncoKB ↗
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. 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met at very strong: c.2052del creates p.Arg686GlyfsTer23, a premature truncation in PALB2, an established loss-of-function disease gene.

PM5Supporting
PM5 · supporting

Met, Supporting: p.Arg686GlyfsTer23 terminates near residue 708, upstream of the PALB2 VCEP cutoff p.Tyr1183.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PALB2 VCEP Rule19 is satisfied by PVS1 (very strong) plus PM5 (supporting).

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
25 / 1,614,070 alleles

gnomAD v4.1: 25 / 1,614,070 alleles. Recorded AF 1.54888e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95355e-06; MAF= 0.00080%, 2/251460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75812e-05; MAF= 0.00176%, 2/113758 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
13 reported laboratory submissions

13 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
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
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 4 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength because NM_024675.4:c.2052del is a truncating frameshift in PALB2, for which loss of function is an established disease mechanism.

PM4 and BP3 are not applicable under the governing PALB2 Version 1.2 specification.

For this frameshift variant, the PALB2-specific codon/residue/domain criteria are limited to PM5 Supporting; PS1, PM1, PP2, and BP1 are not applicable under the governing VCEP rules.

For PALB2 c.2052del (p.Arg686GlyfsTer23), PS2 and PM6 are not applicable under the governing PALB2 VCEP specification.

PP1 and BS4 remain unassessed because the available evidence lacks an exact-variant pedigree and quantitative segregation or non-segregation result.

The PALB2 Version 1.2 VCEP framework governs this evaluation.

PS4 remains not assessed because the available case-control signal is not documented with complete exact-variant metrics required by the VCEP rule.

PP4, PP5, BP5, and BP6 are not applicable under the PALB2 VCEP specification; ClinVar single-submitter assertions do not qualify for PP5 or BP6.

Met · 2

PVS1 Very strongMet at very strong: c.2052del creates p.Arg686GlyfsTer23, a premature truncation in PALB2, an established loss-of-function disease gene. Details ▾Hide ▴
Reasoning

PALB2 loss of function is an established disease mechanism under the PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification. NM_024675.4:c.2052del is a frameshift producing NP_078951.2:p.(Arg686GlyfsTer23), a premature termination signal that removes the distal portion of the PALB2 protein. The assessed transcript is the PALB2 clinical transcript model and is concordant with the governing specification's preferred PALB2 transcript. This is not a canonical splice-site change, and the available evidence provides no indication of a rescue transcript, NMD escape, or a population-enriched loss-of-function region. Under the ClinGen SVI PVS1 framework, no named downgrade rule is triggered; therefore full-strength PVS1 is retained as very strong.

Rule
PALB2 ClinGen/CSPEC Version 1.2 PVS1 guidance, interpreted with the ClinGen SVI PVS1 framework; no applicable downgrade rule identified.
Evidence considered
  • The PALB2 Version 1.2 specification identifies PVS1 as applicable through the PALB2 PVS1 decision tree and identifies PM4 and BP3 as not applicable.
  • The variant is NM_024675.4:c.2052del, a frameshift predicted as NP_078951.2:p.(Arg686GlyfsTer23).
  • PALB2 loss of function is an established disease mechanism in the governing gene-specific framework.
  • ClinGen SVI PVS1 guidance states that frameshift variants can support loss-of-function evidence when the gene-disease mechanism is established and no NMD-escape or non-critical-region downgrade applies.
  • The generic ACMG/AMP guidance states that frameshift variants can disrupt gene function through absence of the altered gene product from transcript loss or nonsense-mediated decay.
Still missing
  • The case materials do not provide an explicit exon number or direct RNA/NMD assay for this transcript.
  • No transcript-specific experimental confirmation of the predicted truncation was identified.
  • These gaps do not trigger a named ClinGen SVI downgrade on the available evidence.
Sources
cspec ↗pvs1_generic_framework ↗PMID:25741868 ↗
PM5 SupportingMet, Supporting: p.Arg686GlyfsTer23 terminates near residue 708, upstream of the PALB2 VCEP cutoff p.Tyr1183. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP defines PM5 at Supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. NM_024675.4:c.2052del produces p.(Arg686GlyfsTer23), terminating at approximately residue 708, upstream of p.Tyr1183; the rule is met.

Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.
Evidence considered
  • The governing PALB2 Version 1.2 PM5 rule applies Supporting evidence to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.
  • Variant normalization predicts p.(Arg686GlyfsTer23), with the premature termination at approximately residue 708, which is upstream of p.Tyr1183.
Sources
cspec ↗

Not met · 4 · evaluated, threshold not reached

PM2 Not met: gnomAD v4.1 total AF is 0.00154888%, above the PALB2 PM2 cutoff of <=0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP specifies PM2 Supporting when frequency is <=0.000333% in gnomAD v4. The gnomAD v4.1 all-comers total AF is 1.54888e-05 (0.00154888%), and grpmax FAF is 1.454e-05 (0.001454%), both above the PM2 cutoff. The non-cancer gnomAD v3.1 genomes-only total AF is 2.02796e-05 (0.00202796%), also above the cutoff; absence in gnomAD v2.1 non-cancer does not override the observed qualifying frequency in the governing default dataset. Therefore PM2 is not met.

Rule
Frequency <= 1/300,000 (0.000333%) in gnomAD v4 dataset
Evidence considered
  • The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification Version 1.2 defines PM2 Supporting as frequency <=0.000333% in the gnomAD v4 dataset.
  • gnomAD v4.1 reports 25/1,614,070 alleles, total AF 1.54888e-05 (0.00154888%), and grpmax FAF 1.454e-05 (0.001454%); both exceed 0.000333%.
  • The non-cancer gnomAD v3.1 genomes-only result is 3/147,932 alleles, total AF 2.02796e-05 (0.00202796%), with grpmax FAF 1.972e-05 (0.001972%), also exceeding the PM2 cutoff.
Sources
cspec ↗gnomad_v4 ↗
BA1 Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BA1 threshold of >0.1%. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP specifies BA1 when gnomAD v4 grpmax filtering AF is >0.1%. The applicable gnomAD v4.1 all-comers grpmax FAF is 1.454e-05 (0.001454%), and the available gnomAD v3.1 non-cancer genomes-only grpmax FAF is 1.972e-05 (0.001972%); both are below 0.1%. Therefore BA1 is not met.

Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
  • The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification Version 1.2 defines BA1 as grpmax filtering AF >0.1% in the gnomAD v4 dataset.
  • gnomAD v4.1 reports 25/1,614,070 alleles, total AF 1.54888e-05, and grpmax FAF 1.454e-05; the highest subpopulation AF is 2.11856e-05 in European (non-Finnish) individuals.
  • The non-cancer subset is also far below BA1: gnomAD v3.1 non-cancer genomes report 3/147,932 alleles, total AF 2.02796e-05, and grpmax FAF 1.972e-05; gnomAD v2.1 non-cancer reports the variant as absent.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: gnomAD v4.1 grpmax FAF is 0.001454%, below the PALB2 BS1 threshold of >0.01%. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP specifies BS1 when gnomAD v4 grpmax filtering AF is >0.01%. The gnomAD v4.1 all-comers grpmax FAF is 1.454e-05 (0.001454%), below 0.01%. The non-cancer gnomAD v3.1 genomes-only grpmax FAF is 1.972e-05 (0.001972%), also below 0.01%, and gnomAD v2.1 non-cancer is absent. Therefore BS1 is not met.

Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
  • The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification Version 1.2 defines BS1 as grpmax filtering AF >0.01% in the gnomAD v4 dataset.
  • gnomAD v4.1 reports 25/1,614,070 alleles, total AF 1.54888e-05, and grpmax FAF 1.454e-05 (0.001454%); the highest subpopulation AF is 2.11856e-05 (0.002119%).
  • The non-cancer subset does not reach BS1: gnomAD v3.1 non-cancer genomes report grpmax FAF 1.972e-05 (0.001972%), while gnomAD v2.1 non-cancer reports absence.
Sources
cspec ↗gnomad_v4 ↗
BS2 Not met: gnomAD v4.1 reports zero homozygotes, providing no PALB2 BS2 points toward the 1-point supporting threshold. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP assigns BS2 from unaffected individuals homozygous for the variant, with 1 point for supporting, 2 points for moderate, and at least 4 points for strong evidence. The variant has zero homozygotes in gnomAD v4.1 all-comers, gnomAD v3.1 non-cancer genomes, and gnomAD v2.1; no qualifying unaffected homozygote observations are available. Therefore BS2 is not met.

Rule
BS2: Strong >=4 points; Moderate =2 points; Supporting =1 point; see PALB2 Fanconi Anemia BS2 tables
Evidence considered
  • The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification defines BS2 as at least 1 point for supporting, 2 points for moderate, or 4 points for strong evidence, using its Fanconi anemia BS2 tables.
  • gnomAD v4.1 reports homozygotes = 0 for the all-comers dataset, including zero homozygotes in the European (non-Finnish) group.
  • The non-cancer datasets also report zero homozygotes: gnomAD v3.1 non-cancer genomes have homozygotes = 0 and gnomAD v2.1 non-cancer reports the variant as absent.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 4 · no assessment recorded

PS4 Not assessed: the exact-variant case-control odds ratio, p-value, and lower 95% confidence bound required by the PALB2 PS4 rule are not available. Details ▾Hide ▴
Reasoning

The PALB2 VCEP permits PS4 only at Strong strength for case-control studies meeting the literal rule: "p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)." The available record reports that this exact variant was observed in multiple affected individuals and references a case-control analysis, but it does not provide a verified exact-variant odds ratio, p-value, or lower 95% confidence bound. The extracted PMID:28779002 evidence is gene-level aggregate data for PALB2 truncating variants (OR 4.69, 95% CI 2.27–9.68, p=6.9×10−6) and explicitly does not report c.2052del, so it cannot be transferred to this variant. Because the exact metrics required by the governing rule are incomplete, PS4 cannot be adjudicated.

Rule
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).
Evidence considered
  • The PALB2 VCEP PS4 Strong rule is case-control studies with p-value ≤.05 and either odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5.
  • The exact variant is reported in ClinVar submissions as occurring in multiple families or individuals with breast cancer, but the available submission text does not provide complete verified exact-variant case-control metrics.
  • PMID:28779002 reports aggregate PALB2 truncating-variant risk in 13,087 cases and 5,488 controls: OR 4.69, 95% CI 2.27–9.68, p=6.9×10−6; the paper does not report c.2052del or p.(R686Gfs*23), so this gene-level result is not sufficient for exact-variant PS4.
Still missing
  • Verified exact-variant case and control counts or an exact-variant odds ratio, hazard ratio, or relative risk
  • Exact-variant p-value and lower 95% confidence bound for comparison with the PALB2 PS4 thresholds
Sources
cspec ↗PMID:28779002 ↗clinvar ↗
PM3 Not assessed: no affected-proband observation or documented phase with a pathogenic PALB2 variant in trans is available for c.2052del. Details ▾Hide ▴
Reasoning

The governing PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, assigns PM3 using Fanconi anemia PM3 point tables: 1 point for supporting, 2 for moderate, at least 4 for strong, and at least 8 for very strong. PALB2 has an autosomal-recessive Fanconi anemia condition, so PM3 would require an affected proband with this variant and a pathogenic or likely pathogenic PALB2 variant demonstrated in trans, or another qualifying phase/inheritance observation under the PM3 tables. The available case evidence documents the target variant as NM_024675.4:c.2052del (p.Arg686GlyfsTer23), but provides no affected-proband record, second pathogenic PALB2 allele, or reliable cis/trans phase information for this variant. The general Fanconi anemia literature reviewed describes biallelic PALB2 disease but does not mention c.2052del and cannot establish PM3 for this allele. Therefore no PM3 points or strength can be assigned.

Rule
PALB2 VCEP v1.2 PM3: assign points using the Fanconi anemia PM3 tables; PM3 Supporting = 1 point, PM3 = 2 points, PM3 Strong = at least 4 points, PM3 Very Strong = at least 8 points.
Evidence considered
  • PALB2 VCEP version 1.2 specifies PM3 point thresholds of 1 point for supporting, 2 points for moderate, at least 4 points for strong, and at least 8 points for very strong, using the Fanconi anemia PM3 tables.
  • The case identifies the variant as NM_024675.4:c.2052del, predicted p.(Arg686GlyfsTer23), but the supplied evidence contains no affected-proband observation, second pathogenic PALB2 allele, or cis/trans phase result.
  • PMID:17200671 reports biallelic PALB2 mutations in Fanconi anemia but its extracted finding does not mention c.2052del; it therefore supplies gene-level context only and not allele-specific PM3 evidence.
Still missing
  • Affected-proband clinical observation for NM_024675.4:c.2052del is not documented.
  • A second pathogenic or likely pathogenic PALB2 variant and its phase relative to c.2052del are not documented.
  • No PM3 Fanconi anemia point-table evidence can be assigned without qualifying biallelic or in-trans observations.
Sources
cspec ↗PMID:17200671 ↗
PP1 Not assessed: no exact-variant pedigree, affected-relative count, LOD score, or Bayes factor is available to compare with the VCEP PP1 thresholds. Details ▾Hide ▴
Reasoning

PP1 is applicable under the PALB2 Version 1.2 VCEP specification, which mandates quantitative co-segregation analysis. The available case evidence does not provide an exact-variant pedigree, affected-relative count with genotypes and phenotypes, LOD score, or Bayes factor. Therefore, PP1 cannot be assigned at supporting, moderate, or strong strength. The VCEP thresholds are supporting at LOD >=0.3 or LR >=2:1, moderate at LOD >=0.60 or LR >=4:1, and strong at LOD >=1.26 or LR >=18:1.

Rule
AD: supporting LOD >=0.3 or LR >=2:1; moderate LOD >=0.60 or LR >=4:1; strong LOD >=1.26 or LR >=18:1. Quantitative co-segregation analysis is mandated.
Evidence considered
  • The PALB2 VCEP mandates quantitative co-segregation analysis for PP1.
  • The VCEP defines PP1 supporting as LOD >=0.3 or LR >=2:1, moderate as LOD >=0.60 or LR >=4:1, and strong as LOD >=1.26 or LR >=18:1.
  • The reviewed exact-variant literature extracts did not provide a c.2052del-specific pedigree or quantitative segregation result.
Still missing
  • Provide an exact-variant pedigree with affected and unaffected relatives, phenotype details, genotype results, and meioses.
  • Calculate quantitative co-segregation evidence as LOD or Bayes factor/LR using the PALB2 VCEP approach.
Sources
cspec ↗PMID:25099575 ↗PMID:25529982 ↗
BS4 Not assessed: no exact-variant non-segregation data or quantitative LOD/LR result is available to compare with the VCEP BS4 thresholds. Details ▾Hide ▴
Reasoning

BS4 is applicable under the PALB2 Version 1.2 VCEP specification, which mandates quantitative co-segregation analysis and cautions that phenocopies and multiple pathogenic variants can mimic lack of segregation. The available case evidence does not provide an exact-variant pedigree, tested affected relatives who lack the variant, LOD score, or Bayes factor. Therefore, BS4 cannot be assigned at supporting, moderate, or strong strength. The VCEP thresholds are supporting at LOD <=-0.32 or LR <=0.48, moderate at LOD <=-0.64 or LR <=0.23, and strong at LOD <=-1.28 or LR <=0.053:1.

Rule
Supporting LOD <=-0.32 or LR <=0.48; moderate LOD <=-0.64 or LR <=0.23; strong LOD <=-1.28 or LR <=0.053:1. Quantitative co-segregation analysis is mandated.
Evidence considered
  • The PALB2 VCEP mandates quantitative co-segregation analysis for BS4 and warns that phenocopies or multiple pathogenic variants can mimic lack of segregation.
  • The VCEP defines BS4 supporting as LOD <=-0.32 or LR <=0.48, moderate as LOD <=-0.64 or LR <=0.23, and strong as LOD <=-1.28 or LR <=0.053:1.
  • The reviewed exact-variant literature extracts did not provide a c.2052del-specific non-segregation observation or quantitative result.
Still missing
  • Provide an exact-variant pedigree identifying affected relatives who test negative, with phenotype, genotype, and meiosis details.
  • Calculate quantitative co-segregation evidence as LOD or Bayes factor/LR and assess phenocopy or alternative-variant explanations.
Sources
cspec ↗PMID:25099575 ↗PMID:25529982 ↗
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.2052del is a coding frameshift, p.Arg686GlyfsTer23, rather than a same-splice-site substitution evaluated by PALB2 PS1. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PS1 only through its PS1 splicing table. NM_024675.4:c.2052del is a coding frameshift, NP_078951.2:p.(Arg686GlyfsTer23), not a missense or splice-altering substitution, so same-splice-site evidence is not applicable.

Rule
Use PALB2 PS1 Splicing table
Evidence considered
  • The governing PALB2 Version 1.2 framework directs PS1 assessment to the PALB2 PS1 Splicing table.
  • The normalized consequence is a frameshift, NM_024675.4:c.2052del, p.(Arg686GlyfsTer23), not a missense substitution or a splice-site variant.
Sources
cspec ↗
PS2 VCEPNot applicable: the PALB2 VCEP explicitly prohibits PS2 because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP specification explicitly prohibits PS2 for both autosomal-dominant PALB2-related cancer predisposition and autosomal-recessive Fanconi anemia because informative de novo occurrences have not been observed and de novo events are unlikely to be informative.

VCEP rule
Do not use for AD or AR disease: informative de novo occurrences have not yet been observed; de novo AR conditions are unlikely to be informed by phase.
Evidence considered
  • The governing PALB2 Version 1.2 specification marks PS2 not applicable and states not to use it for either AD or AR disease.
Sources
cspec ↗
PS3 VCEPNot applicable: PALB2 VCEP specification version 1.2 explicitly designates PS3 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification, version 1.2, explicitly designates PS3 as not applicable for PALB2. Therefore, functional evidence is not adjudicated under PS3 for this variant, regardless of the general ACMG/AMP PS3 definition or the availability of assay-related observations in literature about PALB2 or other variants.

VCEP rule
PALB2 VCEP v1.2: PS3 not applicable.
Evidence considered
  • The PALB2 VCEP specification (version 1.2) lists PS3 applicability as Not applicable and provides no strength rule for PS3.
  • The available literature includes functional observations for other PALB2 loss-of-function variants, but those observations cannot override the governing PALB2-specific PS3 exclusion or be used to adjudicate this criterion.
Sources
cspec ↗
PM1 VCEPNot applicable: PALB2 VCEP PM1 is prohibited because missense pathogenic variation is not confirmed as a disease mechanism. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP marks PM1 as not applicable and states: do not use, because missense pathogenic variation in PALB2 is not yet confirmed as a disease mechanism. This frameshift therefore cannot receive PM1 domain or hotspot evidence.

VCEP rule
Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
Evidence considered
  • The governing PALB2 Version 1.2 framework lists PM1 as not applicable and instructs curators not to use it because missense pathogenic variation in PALB2 is not yet confirmed as a disease mechanism.
  • The variant is a frameshift rather than a missense change.
Sources
cspec ↗
PM4 VCEPNot applicable: the PALB2 Version 1.2 specification explicitly excludes PM4, so this frameshift is evaluated under PVS1 instead. Details ▾Hide ▴
Reasoning

The governing PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification explicitly lists PM4 as not applicable. This frameshift loss-of-function variant is therefore not assessed under PM4, and PVS1 is the applicable consequence criterion.

VCEP rule
PALB2 ClinGen/CSPEC Version 1.2: PM4 not applicable.
Evidence considered
  • The PALB2 Version 1.2 specification explicitly marks PM4 as Not Applicable.
Sources
cspec ↗
PM6 VCEPNot applicable: the PALB2 VCEP explicitly prohibits PM6 for both autosomal-dominant and autosomal-recessive disease. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.2 VCEP specification explicitly marks PM6 not applicable for AD or AR disease because informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informative.

VCEP rule
Do not use for AD or AR disease: informative de novo occurrences have not yet been observed; de novo AR conditions are unlikely to be informed by phase.
Evidence considered
  • The governing PALB2 Version 1.2 specification marks PM6 not applicable and states not to use it for AD or AR disease.
Sources
cspec ↗
PP2 VCEPNot applicable: PALB2 VCEP PP2 is prohibited, and c.2052del is a frameshift rather than a missense variant. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP marks PP2 as not applicable and instructs curators not to use it because missense variation is not yet confirmed or refuted as a disease mechanism for PALB2. The present variant is also a frameshift, not missense.

VCEP rule
Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.
Evidence considered
  • The governing PALB2 Version 1.2 framework lists PP2 as not applicable and says not to use it because missense is not yet confirmed or refuted as a PALB2 disease mechanism.
  • The normalized consequence is p.(Arg686GlyfsTer23), a frameshift.
Sources
cspec ↗
PP3 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP PP3 splice-prediction scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), and the PALB2 VCEP specifies PP3 for predicted splice impact in silent, missense/in-frame, and eligible intronic variants, not frameshift variants. The computational predictor scores were therefore not evaluated for PP3.

Rule
PALB2 VCEP Version 1.2 PP3: predicted splice impact via SpliceAI >=0.2 for silent, missense/in-frame, and eligible intronic variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework classifies this variant as a frameshift and limits PP3 splice-prediction use to silent, missense/in-frame, and eligible intronic variants.
Sources
cspec ↗
PP4 VCEPNot applicable: the PALB2 VCEP excludes PP4 for autosomal-dominant breast cancer because the phenotype is not sufficiently specific. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PP4 as not applicable for autosomal-dominant PALB2-related cancer predisposition because breast cancer has multiple genetic etiologies and no phenotype features reliably distinguish hereditary from sporadic disease. The variant is being evaluated in the dominant PALB2 cancer-predisposition context, so generic PP4 is not used.

VCEP rule
Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology and there are no features that can readily distinguish hereditary from sporadic causes.
Evidence considered
  • The PALB2 VCEP states: do not use PP4 for autosomal-dominant disease because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.
Sources
cspec ↗
PP5 VCEPNot applicable: PALB2 excludes PP5, and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PP5 as not applicable and states that the criterion is not for use. Although the exact variant has Pathogenic single-submitter ClinVar assertions, the ClinVar audit identifies zero expert-panel submissions; ordinary laboratory submissions and the aggregate ClinVar label therefore do not qualify under the required exact-variant expert-panel rule.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PALB2 VCEP states that PP5 is not for use.
  • The exact-variant ClinVar audit reports 13 submissions, all single-submitter laboratory assertions, and zero expert-panel submissions; the aggregate classification is Pathogenic but is not eligible for PP5.
Sources
cspec ↗clinvar ↗
BS3 VCEPNot applicable: PALB2 VCEP specification version 1.2 explicitly designates BS3 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification, version 1.2, explicitly designates BS3 as not applicable for PALB2. Therefore, benign functional assay evidence is not adjudicated under BS3 for this variant, regardless of the general ACMG/AMP BS3 definition or the absence of a variant-specific benign assay result.

VCEP rule
PALB2 VCEP v1.2: BS3 not applicable.
Evidence considered
  • The PALB2 VCEP specification (version 1.2) lists BS3 applicability as Not applicable and provides no strength rule for BS3.
  • No benign functional result is needed to resolve this criterion because the governing PALB2-specific framework excludes BS3 from use.
Sources
cspec ↗
BP1 N/ANot applicable: BP1 is restricted to missense variants, whereas c.2052del produces the frameshift p.Arg686GlyfsTer23. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP limits BP1 Supporting evidence to all missense variants. NM_024675.4:c.2052del is a coding frameshift producing p.(Arg686GlyfsTer23), so BP1 does not apply.

Rule
Apply to all missense variants.
Evidence considered
  • The governing PALB2 Version 1.2 BP1 rule says to apply Supporting BP1 to all missense variants.
  • The normalized consequence is a frameshift, NM_024675.4:c.2052del, p.(Arg686GlyfsTer23), not a missense variant.
Sources
cspec ↗
BP2 VCEPNot applicable: PALB2 VCEP version 1.2 explicitly designates BP2 as not applicable. Details ▾Hide ▴
Reasoning

The governing PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, explicitly designates BP2 as not applicable. Accordingly, BP2 is not evaluated for this PALB2 variant, regardless of whether cis or trans observations are available.

VCEP rule
BP2 is not applicable under the PALB2 VCEP version 1.2 specification.
Evidence considered
  • PALB2 VCEP version 1.2 lists BP2 as Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: PALB2 Version 1.2 excludes BP3, and this variant is a protein-truncating frameshift rather than a benign repeat-region indel. Details ▾Hide ▴
Reasoning

The governing PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification explicitly lists BP3 as not applicable. In addition, the variant is a protein-truncating frameshift rather than an in-frame deletion or insertion confined to a repetitive region without expected functional impact.

VCEP rule
PALB2 ClinGen/CSPEC Version 1.2: BP3 not applicable.
Evidence considered
  • The PALB2 Version 1.2 specification explicitly marks BP3 as Not Applicable.
  • The variant consequence is frameshift with a premature termination signal, not an in-frame repeat-region indel.
Sources
cspec ↗
BP4 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP BP4 splice-prediction scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), and the PALB2 VCEP specifies BP4 for no predicted splice impact in splicing variants, explicitly excluding missense variants and not extending the rule to frameshift variants. The SpliceAI score was therefore not evaluated for BP4.

Rule
PALB2 VCEP Version 1.2 BP4: no predicted splice impact via SpliceAI <=0.1 for splicing variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework limits BP4 to no predicted splice impact for splicing variants and does not apply it to this frameshift consequence.
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP excludes BP5 because co-occurring pathogenic variants do not reliably alter the phenotype in this moderate-penetrance disorder. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP5 as not applicable and instructs that it should not be used because multiple pathogenic variants can co-occur without a noticeably different phenotype and PALB2 has moderate penetrance. No alternate molecular basis is needed for this criterion because the governing PALB2 specification excludes BP5.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance.
Evidence considered
  • The PALB2 VCEP states: do not use BP5 because cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype and PALB2 has moderate penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: PALB2 excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign classification exists. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP6 as not applicable and states that the criterion is not for use. The exact variant has no ClinVar expert-panel Benign or Likely benign classification; the available exact-variant assertions are single-submitter laboratory Pathogenic classifications, which cannot trigger BP6.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PALB2 VCEP states that BP6 is not for use.
  • The exact-variant ClinVar audit reports zero expert-panel submissions and only single-submitter laboratory Pathogenic assertions, so no qualifying Benign or Likely benign expert-panel assertion is present.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is not synonymous and is outside the PALB2 VCEP BP7 scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), not a synonymous variant. The PALB2 VCEP BP7 rule is restricted to synonymous and specified deep intronic variants, so no BP7 assessment was performed.

Rule
PALB2 VCEP Version 1.2 BP7: use for synonymous and specified deep intronic variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework restricts BP7 to synonymous and specified deep intronic variants; this variant is a frameshift.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.2052del
Protein (HGVS p.)
NP_078951.2:p.(Arg686GlyfsTer23)
GRCh38
chr16:23630101 TG>T
GRCh37
chr16:23641422 TG>T
Location and type
Exon 5 · frameshift
ClinVar
142733

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…
gnomAD v4.1 25 / 1,614,070 alleles AF 1.55e-05 · 0 homozygotes · FAF 1.45e-05
gnomAD v2.1 2 / 251,460 alleles AF 7.95e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.5e-05 · 25 / 1,614,070 alleles · 0 hom · FAF 1.5e-05
European (non-Finnish)25 / 1,180,048 2.1e-05
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.

gnomAD v2.1

AF 8e-06 · 2 / 251,460 alleles · 0 hom · FAF 2.9e-06
European (non-Finnish)2 / 113,758 1.8e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.54888e-05; MAF= 0.00155%, 25/1614070 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.11856e-05; MAF= 0.00212%, 25/1180048 alleles, homozygotes = 0); grpmax FAF= 1.454e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95355e-06; MAF= 0.00080%, 2/251460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75812e-05; MAF= 0.00176%, 2/113758 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +229 bp
0.020
SpliceAI acceptor gainat +271 bp
0.000
SpliceAI donor lossat +327 bp
0.002
SpliceAI donor gainat -141 bp
0.001
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.021

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP PP3 splice-prediction scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), and the PALB2 VCEP specifies PP3 for predicted splice impact in silent, missense/in-frame, and eligible intronic variants, not frameshift variants. The computational predictor scores were therefore not evaluated for PP3.

Rule
PALB2 VCEP Version 1.2 PP3: predicted splice impact via SpliceAI >=0.2 for silent, missense/in-frame, and eligible intronic variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework classifies this variant as a frameshift and limits PP3 splice-prediction use to silent, missense/in-frame, and eligible intronic variants.
Sources
cspec ↗
BP4 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is outside the PALB2 VCEP BP4 splice-prediction scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), and the PALB2 VCEP specifies BP4 for no predicted splice impact in splicing variants, explicitly excluding missense variants and not extending the rule to frameshift variants. The SpliceAI score was therefore not evaluated for BP4.

Rule
PALB2 VCEP Version 1.2 BP4: no predicted splice impact via SpliceAI <=0.1 for splicing variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework limits BP4 to no predicted splice impact for splicing variants and does not apply it to this frameshift consequence.
Sources
cspec ↗
BP7 N/ANot applicable: the frameshift consequence p.(Arg686GlyfsTer23) is not synonymous and is outside the PALB2 VCEP BP7 scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_024675.4:c.2052del is a frameshift variant, p.(Arg686GlyfsTer23), not a synonymous variant. The PALB2 VCEP BP7 rule is restricted to synonymous and specified deep intronic variants, so no BP7 assessment was performed.

Rule
PALB2 VCEP Version 1.2 BP7: use for synonymous and specified deep intronic variants; frameshift variants are outside scope.
Evidence considered
  • The PALB2 Version 1.2 VCEP framework restricts BP7 to synonymous and specified deep intronic variants; this variant is a frameshift.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

8 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • 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.
    The ACMG/AMP consensus guideline describes frameshift variants as variants that can disrupt gene function by causing absence of the gene product through lack of transcription or nonsense-mediated decay, while emphasizing that gene-disease mechanism and variant context must be considered.
    → PVS1 · very strong Does not name this variant
    PMID 25741868 ↗
    Source detail
    Certain types of variants (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript.

    Location Section: Proposed criteria for interpretation of sequence variants; subsection: PVS1 null variants

    Context Consensus guideline and framework discussion; this paper does not report the case variant specifically.

Other recorded publications

  • Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
    No paper-specific finding is recorded.
    PMID 18053174 ↗
  • A novel PALB2 truncating mutation in an Italian family with male breast cancer.
    This study assessed segregation of a different PALB2 truncating variant in a family with male breast cancer, but it did not report PALB2 c.2052del or p.(Arg686GlyfsTer23), so it does not provide segregation evidence for this case.
    Does not name this variant
    PMID 25529982 ↗
    Quoted passage
    The novel mutation c.1285_1286delAinsTC (p.I429SfsX12) was found to be localized in exon 4 of PALB2, in the region that encodes for the ChAM motif (Fig. 3).

    Discussion, paragraph 5; Results, paragraphs 3-4; Table I and Figure 3

  • PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.
    No paper-specific finding is recorded.
    PMID 28279176 ↗
  • Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
    Decker B et al. · 2017
    This population-based case-control study evaluated PALB2 protein-truncating variants collectively in 13,087 breast cancer cases and 5,488 controls. The aggregate PALB2 truncating-variant group was associated with increased breast cancer risk, but the study did not report NM_024675.4:c.2052del or NP_078951.2:p.(R686Gfs*23) specifically.
    Does not name this variant
    PMID 28779002 ↗
    Quoted passage
    Of the four genes, truncating variants in PALB2 were associated with the highest BC risk, with an estimated OR=4.69 (95% CI 2.27 to 9.68, p=6.9×10−6)(table 1 and figure 2). Most truncating variants were rare, with 19/35 (54%) observed as singletons.

    Results, ‘BC risks associated with ATM, CHEK2 and PALB2 truncating variants’; Table 1 and Figure 2

  • The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.
    No paper-specific finding is recorded.
    PMID 28858227 ↗
  • Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.
    Reid S et al. · 2007
    No paper-specific finding is recorded.
    PMID 17200671 ↗
  • Breast-cancer risk in families with mutations in PALB2.
    Antoniou AC et al. · 2014
    This study analyzed inherited PALB2 loss-of-function mutations in 154 families comprising 362 mutation carriers and estimated breast-cancer risk, but it did not report PALB2 c.2052del or provide variant-specific segregation data for this case.
    Does not name this variant
    PMID 25099575 ↗
    Quoted passage
    We estimated the risk of breast cancer for PALB2 mutation carriers, using data from 154 families with 362 members who had loss-of-function mutations in this gene.

    Discussion

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 25 / 1,614,070 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 13 Pathogenic 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

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= 1.54888e-05; MAF= 0.00155%, 25/1614070 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.11856e-05; MAF= 0.00212%, 25/1180048 alleles, homozygotes = 0); grpmax FAF= 1.454e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95355e-06; MAF= 0.00080%, 2/251460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75812e-05; MAF= 0.00176%, 2/113758 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories). (ClinVarID = 142733)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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.