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PALB2c.1592delPathogenic
Print report
Variant interpretation report

PALB2 c.1592del, p.Leu531CysfsTer30

NM_024675.4:c.1592del NP_078951.2:p.(Leu531CysfsTer30) Frameshift · exon 4 View identifiers
Classification
Pathogenic

Variant description:

The PALB2 NM_024675.4:c.1592del (NP_078951.2:p.(Leu531CysfsTer30)) frameshift variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen; ClinVar ID 126609).

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.

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 v1.3. 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Met, very strong: the exon 4 frameshift creates p.(Leu531CysfsTer30), a premature stop upstream of c.3301 on the clinically relevant PALB2 transcript.

PS4Strong
PS4 · strong

Met at Strong: Finnish case-control data reported p=0.005, OR=11.3, and 95% CI 1.8–57.8, satisfying p≤.05 and OR≥3.

PP5Supporting
PP5 · supporting

Not applicable: the PALB2 VCEP explicitly states that PP5 is not for use.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 (very strong) plus PS4 (strong) satisfy Rule1 of the PALB2 Version 1.3 VCEP framework.

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
116 / 1,613,984 alleles

gnomAD v4.1: 116 / 1,613,984 alleles. Recorded AF 7.18718e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000173213; MAF= 0.01732%, 49/282888 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00187102; MAF= 0.18710%, 47/25120 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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

Recorded SpliceAI maximum delta score: 0.029. Refer to the recorded PP3/BP4 rationale for interpretation.

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

14 Pathogenic · 1 pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → 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 v1.3, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 3 not met · 5 not assessed · 17 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

PS4 is met at Strong because exact-variant Finnish case-control data report p=0.005 and OR=11.3 with 95% CI 1.8–57.8, satisfying the PALB2 VCEP PS4 rule.

PP4, PP5, BP5, and BP6 are not applicable under the PALB2 VCEP's own specifications.

Met · 3

PVS1 Very strongVCEPMet, very strong: the exon 4 frameshift creates p.(Leu531CysfsTer30), a premature stop upstream of c.3301 on the clinically relevant PALB2 transcript. Details ▾Hide ▴
Reasoning

NM_024675.4:c.1592del is a frameshift variant producing NP_078951.2:p.(Leu531CysfsTer30) / p.(L531Cfs*30) in exon 4 of the clinically relevant PALB2 transcript. The premature termination codon is upstream of c.3301 and therefore follows the PALB2 VCEP's NMD-prone frameshift path for full-strength PVS1. The VCEP states that all presumed loss-of-function events occur in biologically relevant transcripts and that PALB2 loss of function is an established disease mechanism. No specific downgrade rule applies. The exact variant was searched under c.1592del, p.Leu531CysfsTer30, and p.L531Cfs*30; no exact variant row was found in PALB2_PVS1_v1.3.pdf.txt, so the governing generic decision-tree row was applied.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... Nonsense or frameshift | Predicted to undergo NMD (introduction of a premature termination codon between p.Asp2 and Leu1101/upstream of c.3301) | PVS1
Evidence considered
  • PALB2 PVS1 v1.3 decision tree, page 4, NMD-prone frameshift row: a nonsense or frameshift predicted to undergo NMD with a premature termination codon between p.Asp2 and Leu1101/upstream of c.3301 receives PVS1.
  • Case consequence facts: NM_024675.4:c.1592del; NP_078951.2:p.(Leu531CysfsTer30) / p.(L531Cfs*30); exon 4; frameshift.
  • PALB2 PVS1 v1.3 transcript note: NM_024675.3/ENST00000261584.8 is the clinically relevant reference transcript and no alternate rescue transcript is considered biologically relevant.
  • PMID:18053174, Discussion: the exact c.1592delT/L531fs allele is described as a truncating PALB2 mutation; this is concordant with the normalized frameshift consequence but does not replace the VCEP decision tree.
Still missing
  • No exact entry for c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30 was found in PALB2_PVS1_v1.3.pdf.txt; the applicable generic NMD-prone frameshift row was present and used.
Sources
cspec ↗vcep_palb2_pvs1_v1_3 ↗pvs1_variant_assessmentpvs1_gene_contextPMID:18053174 ↗
PS4 StrongVCEPMet at Strong: Finnish case-control data reported p=0.005, OR=11.3, and 95% CI 1.8–57.8, satisfying p≤.05 and OR≥3. Details ▾Hide ▴
Reasoning

The PALB2 VCEP requires case-control studies with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥3 or a lower 95% confidence interval ≥1.5. The exact c.1592delT variant was evaluated in a Finnish case-control comparison: familial breast-cancer cases carried the variant in 3/113 (2.7%) versus 6/2,501 controls (0.2%), with reported p=0.005, OR=11.3, and 95% CI 1.8–57.8; the paper's abstract also describes significant enrichment versus ancestry-matched population controls. In the same paper's unselected breast-cancer analysis, the variant occurred in 18 additional cases and was significantly associated with breast cancer at 0.9% versus 0.2% in 2,051 controls, p=0.003, OR=3.94, 95% CI 1.5–12.1. The independent penetrance study of the exact variant estimated HR=6.1, 95% CI 2.2–17.2, p=0.01. Each reported comparison satisfies the VCEP rule; the familial case-control result alone satisfies both the p-value and effect-size requirements.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥3 **or** lower 95% CI ≥1.5).
Evidence considered
  • ClinGen PALB2 VCEP CSPEC PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5).
  • Erkko et al., Nature 2007, PMID:17287723, Table 1, row PALB2 c.1592delT: familial cases 3/113 (2.7%), controls 6/2,501 (0.2%), p=0.005, OR=11.3, 95% CI 1.8–57.8.
  • Erkko et al., Nature 2007, unselected breast-cancer analysis: 0.9% of cases versus 0.2% of 2,051 controls, p=0.003, OR=3.94, 95% CI 1.5–12.1.
  • Erkko et al., Clinical Cancer Research 2008, PMID:18628482, abstract/results: exact c.1592delT carriers had HR=6.1 for breast cancer, 95% CI 2.2–17.2, p=0.01; the study used modified segregation analyses of Finnish carrier families identified from unselected breast-cancer cases.
Sources
cspec ↗PMID:17287723 ↗PMID:18628482 ↗
PP5 SupportingVCEPNot applicable: the PALB2 VCEP explicitly states that PP5 is not for use. Details ▾Hide ▴
Reasoning

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen PALB2 VCEP PP5 instruction: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 3 · evaluated, threshold not reached

PM2 VCEPNot met: the highest gnomAD v4.1 subpopulation AF is 0.174978% in Finnish individuals, exceeding the PALB2 VCEP PM2 threshold of 0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP permits PM2_supporting when frequency is <=0.000333% in the gnomAD subpopulation with the highest frequency, or under its stated single-observation exception. The default all-comers gnomAD v4.1 record is applicable because the VCEP rule does not specify a non-cancer or exome-only source. The highest-frequency subpopulation is European (Finnish), with AF 0.00174978 (0.174978%), based on 112/64008 alleles; this exceeds 0.000333%, is not a single observation, and the variant is present in other subpopulations. Therefore PM2 is not met.

VCEP rule
Frequency ≤ 1/300,000 (**0.000333%**) in gnomAD subpopulation with the highest frequency ... Exception: If >0.000333% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2\_supporting would apply.
Evidence considered
  • PALB2 VCEP CSPEC PM2 rule: frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; the exception requires >0.000333% but n=1 in a single subpopulation and absence from all others.
  • gnomAD v4.1 all-comers record for PALB2 c.1592del / 16-23634953-CA-C: European (Finnish) is the highest-frequency subpopulation at AF 0.0017497813 (0.174978%), 112/64008 alleles, homozygotes = 0; total AF is 7.18718e-05 (116/1613984 alleles).
Sources
cspec ↗gnomad_v4 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 6.8e-07 (0.000068%), below the PALB2 VCEP BA1 threshold of >0.1%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP defines BA1 as met only when the gnomAD grpmax Filtering AF is >0.1%. The default all-comers gnomAD v4.1 record is the applicable source because the VCEP rule does not specify a non-cancer or exome-only source. Its grpmax FAF is 6.8e-07 (0.000068%), far below 0.1%; therefore BA1 is not met. The gnomAD v2.1 all-comers record likewise has no grpmax FAF value, so it does not override the v4.1 result.

VCEP rule
Grpmax Filtering AF **>.1%** in gnomAD
Evidence considered
  • PALB2 VCEP CSPEC BA1 rule: Grpmax Filtering AF >0.1% in gnomAD.
  • gnomAD v4.1 all-comers record for PALB2 c.1592del / 16-23634953-CA-C: grpmax FAF = 6.8e-07 (0.000068%), with total AF = 7.18718e-05 and European (Finnish) subpopulation AF = 0.00174978.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 6.8e-07 (0.000068%), below the PALB2 VCEP BS1 threshold of >0.01%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP defines BS1 as met when the gnomAD grpmax Filtering AF is >0.01%. The default all-comers gnomAD v4.1 record is the applicable source because the VCEP rule does not specify a non-cancer or exome-only source. Its grpmax FAF is 6.8e-07 (0.000068%), below 0.01%; therefore BS1 is not met.

VCEP rule
Grpmax Filtering AF **>.01%** in gnomAD
Evidence considered
  • PALB2 VCEP CSPEC BS1 rule: Grpmax Filtering AF >0.01% in gnomAD.
  • gnomAD v4.1 all-comers record for PALB2 c.1592del / 16-23634953-CA-C: grpmax FAF = 6.8e-07 (0.000068%).
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PM3 VCEPNot assessed: no governing-table entry or documented Fanconi-anemia observation establishes this allele in trans with a pathogenic variant. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PM3 rule requires a recessive-disease observation with the variant detected in trans with a pathogenic variant and assigns points from Fanconi-anemia proband observations. The governing PALB2_PM3_BS2_1.3.pdf table was searched for c.1592del, p.Leu531CysfsTer30, and p.L531Cfs*30, with no matching entry. The available case evidence documents the Finnish breast-cancer founder allele but does not document a Fanconi-anemia proband, a pathogenic allele in trans, phase, or a homozygous observation. Therefore, no VCEP PM3 points or strength can be assigned.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
  • PALB2_PM3_BS2_1.3.pdf, searched notations c.1592del, p.Leu531CysfsTer30, and p.L531Cfs*30: no matching row found.
  • The case evidence identifies c.1592delT as a Finnish breast-cancer founder mutation, but provides no Fanconi-anemia proband, in-trans pathogenic variant, phase, or homozygous observation for this allele.
  • The VCEP CSPEC entry defines PM3 point strengths as Supporting = 1 point, Moderate = 2 points, Strong = at least 4 points, and Very Strong = at least 8 points; no qualifying points are available here.
Still missing
  • No entry for c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30 was found in PALB2_PM3_BS2_1.3.pdf.
  • A documented Fanconi-anemia proband observation with phase or homozygosity and the other allele's VCEP classification is required.
Sources
vcep_palb2_pm3_bs2_1_3 ↗cspec ↗
PM5 VCEPNot assessed: PM5 requires PVS1 at Very Strong, but the available evidence does not provide that required PVS1 strength determination. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PM5 rule requires a DNA truncating variant to be NMD-prone, receive PVS1 at Very Strong, and have a premature termination codon upstream of p.His1184. The available variant facts establish a frameshift at p.Leu531CysfsTer30, but do not establish an applied PVS1 Very Strong determination; therefore the VCEP PM5 condition cannot be completed without substituting an unpermitted PVS1 assessment.

VCEP rule
* DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.His1184 * Splice Variants: Apply to all observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.His1184. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
  • vcep_materials.json cspec criterion entry for PM5: DNA variants must be NMD-prone, truncating, receive PVS1 at VeryStrong, and have premature termination codons upstream of p.His1184.
  • pvs1_variant_assessment.json identifies the variant as a frameshift, p.(L531Cfs*30), in exon 4, but does not assign PVS1 strength.
Still missing
  • A VCEP-governed determination that this variant receives PVS1 at Very Strong is not available in the supplied evidence.
Sources
cspec ↗pvs1_variant_assessment
PP1 VCEPNot assessed: segregation was reported, but no VCEP-required PP1 LOD or Bayes factor was provided. Details ▾Hide ▴
Reasoning

The PALB2 VCEP applies PP1 using quantitative segregation evidence for autosomal dominant disease: Strong requires LOD ≥1.26 or Bayes Factor (LR) ≥18:1, Moderate requires LOD ≥0.60 or Bayes Factor (LR) ≥4:1, and Supporting requires LOD ≥0.3 or Bayes Factor (LR) ≥2:1. Erkko et al. reported a multigenerational prostate-cancer family in which the c.1592delT allele segregated and stated that all but one male carrier developed prostate cancer by age 76, but no PP1 LOD or Bayes factor was reported. Erkko et al. also performed modified segregation analyses in 17 Finnish probands and their families, estimating breast-cancer hazard ratios, but those hazard ratios are not the VCEP's specified PP1 LOD or Bayes-factor inputs. The available evidence therefore does not permit a VCEP-compliant PP1 strength assignment.

VCEP rule
* AD Condition: LOD ≥1.26 or Bayes Factor (LR) ≥18:1 ... * AD Condition: LOD ≥.60 or Bayes Factor (LR) ≥4:1 ... * AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1
Evidence considered
  • PALB2 Version 1.3 CSPEC PP1 table: autosomal-dominant Supporting requires LOD ≥0.3 or Bayes Factor (LR) ≥2:1; Moderate requires LOD ≥0.60 or Bayes Factor (LR) ≥4:1; Strong requires LOD ≥1.26 or Bayes Factor (LR) ≥18:1.
  • Erkko et al. 2007, A recurrent mutation in PALB2 in Finnish cancer families, lines 11-12: one multigenerational prostate-cancer family segregated the c.1592delT truncation allele.
  • Erkko et al. 2007, Figure 3 caption: the pedigree shows c.1592delT carrier and noncarrier status; all but one male carrier developed prostate cancer by age 76, and DNA was unavailable from the first-generation male ancestor.
  • Erkko et al. 2008, Penetrance analysis of the PALB2 c.1592delT founder mutation, Experimental Design and Methods: modified segregation analyses used 17 carrier probands, available relatives, pedigree data, and maximum-likelihood modeling; the reported outputs were hazard ratios rather than PP1 LOD or Bayes factors.
Still missing
  • A VCEP-compatible PP1 LOD or Bayes factor for the reported segregation evidence is not available.
Sources
cspec ↗PMID:17287723 ↗PMID:18628482 ↗
BS2 VCEPNot assessed: no matching entry was found in PALB2_PM3_BS2_1.3.pdf, and the VCEP excludes gnomAD population cohorts from BS2. Details ▾Hide ▴
Reasoning

The PALB2 VCEP requires BS2 points to be assigned from its Fanconi Anemia BS2 tables and says not to use population-based cohorts such as gnomAD. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.1592del, p.Leu531CysfsTer30, and p.L531Cfs*30; no entry for this variant was found. The available gnomAD records show zero homozygotes but cannot be used for BS2 under the VCEP rule, and no eligible table-based proband points are available.

VCEP rule
See **Fanconi Anemia BS2 tables** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. ... Do not use for individuals in population based cohorts, such as gnomAD
Evidence considered
  • PALB2 VCEP CSPEC BS2 instructions: use the Fanconi Anemia BS2 tables for proband points; do not use individuals in population-based cohorts such as gnomAD.
  • PALB2_PM3_BS2_1.3.pdf was searched for the three specified variant notations; no matching row was found.
  • gnomAD v4.1 all-comers record reports homozygotes = 0, but this population-based observation is not eligible for BS2 under the VCEP rule.
Still missing
  • No entry for c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30 was found in PALB2_PM3_BS2_1.3.pdf; eligible Fanconi Anemia BS2 table observations or proband-level points are therefore unavailable.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3 ↗gnomad_v4 ↗
BS4 VCEPNot assessed: no VCEP-required negative-segregation LOD or Bayes factor was reported. Details ▾Hide ▴
Reasoning

The PALB2 VCEP requires quantitative non-segregation evidence for BS4: Strong requires LOD ≤−1.28 or Bayes Factor (LR) ≤.053:1, Moderate requires LOD ≤−.64 or Bayes Factor (LR) ≤.23, and Supporting requires LOD ≤−.32 or Bayes Factor (LR) ≤.48. The available reports describe segregation analyses and carrier families but do not provide a negative segregation LOD or Bayes factor meeting any BS4 threshold. BS4 therefore cannot be assessed under the VCEP specification.

VCEP rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 LOD ≤ -.64 or Bayes Factor (LR) ≤.23 LOD ≤-.32 or Bayes Factor (LR) ≤.48
Evidence considered
  • PALB2 Version 1.3 CSPEC BS4 table: Strong requires LOD ≤−1.28 or Bayes Factor (LR) ≤.053:1; Moderate requires LOD ≤−.64 or Bayes Factor (LR) ≤.23; Supporting requires LOD ≤−.32 or Bayes Factor (LR) ≤.48.
  • Erkko et al. 2007 and Erkko et al. 2008 report positive carrier-family segregation observations and modified segregation risk analyses, but neither reports a negative-segregation LOD or Bayes factor for this allele.
Still missing
  • A VCEP-compatible negative-segregation LOD or Bayes factor is not available.
Sources
cspec ↗PMID:17287723 ↗PMID:18628482 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: this frameshift is neither a missense nor a splicing variant, the only variant classes covered by PALB2 PS1 guidance. Details ▾Hide ▴
Reasoning

The variant is a frameshift (NP_078951.2:p.(Leu531CysfsTer30)), not a missense or splice variant. The PALB2 VCEP PS1 specification states that missense changes are not to be used and directs the PS1 table to splicing variants; the searched PS1 table contained no entry for c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30.

VCEP rule
• Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. ... • Splicing: Use PALB2 PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.
Evidence considered
  • vcep_materials.json cspec entry for PS1: the VCEP lists missense as not to be used and directs splicing assessment to the PALB2 PS1 Splicing table.
  • PALB2_PS1_1.3.pdf, page 1, PS1 section: the missense and splicing applicability statements and PS1 splicing table were consulted; no row matched c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30.
  • pvs1_variant_assessment.json identifies NM_024675.4:c.1592del as a frameshift in exon 4.
Still missing
  • No entry for c.1592del, p.Leu531CysfsTer30, or p.L531Cfs*30 was found in PALB2_PS1_1.3.pdf.txt.
Sources
cspec ↗vcep_palb2_ps1_1_3 ↗pvs1_variant_assessment
PS2 VCEPNot applicable: the PALB2 VCEP specification explicitly marks PS2 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specification marks PS2 as not applicable; therefore de novo evidence is not evaluated under this framework.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 Version 1.3 CSPEC criterion entry for PS2: applicability is "Not Applicable".
Sources
cspec ↗
PS3 VCEPNot applicable: the PALB2 Version 1.3 VCEP specification explicitly marks PS3 not applicable, regardless of available functional assay evidence. Details ▾Hide ▴
Reasoning

Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 Version 1.3 specification, PS3 is explicitly marked not applicable. Therefore, functional evidence showing a damaging effect, including the reported statement that PALB2 c.1592delT produces a stable but functionally defective product, cannot be assigned to PS3 under this VCEP framework.

VCEP rule
Not applicable
Evidence considered
  • ClinGen PALB2 Version 1.3 CSPEC entry for PS3: applicability is "Not applicable".
  • Erkko et al. 2008, PMID:18628482, Results/Discussion: "The c.1592delT mutation produces a stable but functionally defective product (9)"; this evidence was not assigned because the VCEP marks PS3 not applicable.
Sources
cspec ↗PMID:18628482 ↗
PM1 VCEPNot applicable: the PALB2 VCEP explicitly marks PM1 as Not Applicable, and no approved PALB2 domain table is supplied. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC entry explicitly marks PM1 as Not Applicable. The case's vcep_materials.json domain_tables object is empty, so there is no authoritative PALB2 critical-domain list to evaluate for this variant.

VCEP rule
Not Applicable
Evidence considered
  • vcep_materials.json cspec criterion entry for PM1: applicability is "Not Applicable".
  • vcep_materials.json domain_tables: no PALB2 domain-table entry is present.
Sources
cspec ↗
PM4 VCEPNot applicable: PALB2 VCEP PM4 is restricted to stop-loss variants, whereas this variant is a frameshift deletion. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PM4 not applicable and instructs that it is not used for in-frame insertions or deletions smaller than a single exon and is used only for stop-loss variants. This variant is a frameshift deletion, not a stop-loss or qualifying in-frame alteration.

VCEP rule
Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.
Evidence considered
  • PALB2 VCEP CSPEC PM4 entry: applicability is Not applicable; instructions state, "Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only."
Sources
cspec ↗
PM6 VCEPNot applicable: the PALB2 VCEP specification explicitly marks PM6 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specification marks PM6 as not applicable; therefore assumed de novo evidence is not evaluated under this framework.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 Version 1.3 CSPEC criterion entry for PM6: applicability is "Not Applicable".
Sources
cspec ↗
PP2 VCEPNot applicable: the PALB2 VCEP explicitly marks PP2 as Not Applicable for this gene framework. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC entry explicitly marks PP2 as Not Applicable. No independent missense-mechanism assessment can override that VCEP applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • vcep_materials.json cspec criterion entry for PP2: applicability is "Not Applicable".
Sources
cspec ↗
PP3 N/ANot applicable: c.1592del is an exonic frameshift, outside PP3's VCEP scope for silent, missense/in-frame, or qualifying intronic variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PP3 splicing path covers silent, missense/in-frame, and intronic variants outside donor and acceptor sites, while NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)); therefore PP3 is outside its governing scope. The available SpliceAI max delta of 0.029 is not used because this variant type is not covered by the PP3 rule.

VCEP rule
* Missense: Do not use. * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
  • SpliceAI max delta score = 0.029; this score is not evidence for PP3 because the VCEP PP3 splicing rule does not cover exonic frameshift variants.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for dominant PALB2 cancer predisposition because breast cancer lacks a sufficiently specific phenotype. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PP4 not applicable for autosomal-dominant disease because breast cancer has genetic heterogeneity and no features readily distinguish hereditary from sporadic causes; for autosomal-recessive disease it directs phenotype considerations to PM3 instead.

VCEP rule
Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disorder, use PM3 for specific phenotype considerations
Evidence considered
  • ClinGen PALB2 VCEP PP4 instruction: do not use for autosomal-dominant disease because breast cancer has multiple genetic etiologies and no readily distinguishing features; for autosomal-recessive disease, use PM3 for phenotype considerations.
Sources
cspec ↗
BS3 VCEPNot applicable: the PALB2 Version 1.3 VCEP specification explicitly marks BS3 not applicable, so no benign functional strength can be assigned. Details ▾Hide ▴
Reasoning

Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 Version 1.3 specification, BS3 is explicitly marked not applicable. Consequently, no benign functional interpretation can be assigned under BS3, even though the available evidence does not provide a validated assay demonstrating no damaging effect for this variant.

VCEP rule
Not applicable
Evidence considered
  • ClinGen PALB2 Version 1.3 CSPEC entry for BS3: applicability is "Not applicable".
Sources
cspec ↗
BP1 N/ANot applicable: BP1 is limited to missense variants, whereas this variant is a frameshift at p.Leu531CysfsTer30. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP1 rule applies to all missense variants. This variant is a frameshift, not a missense variant, so the stated applicability condition is not met.

VCEP rule
Apply to all missense variants.
Evidence considered
  • vcep_materials.json cspec criterion entry for BP1: "Apply to all missense variants."
  • pvs1_variant_assessment.json identifies the variant consequence class as frameshift.
Sources
cspec ↗pvs1_variant_assessment
BP2 VCEPNot applicable: the PALB2 VCEP explicitly designates BP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC entry explicitly marks BP2 as Not Applicable. No alternative ACMG/AMP rule is used.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 VCEP CSPEC criterion entry for BP2: applicability = Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: PALB2 VCEP BP3 is not used for small in-frame losses or repetitive regions, and this variant is a frameshift. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP3 not applicable. It specifically states that small in-frame losses are neither confirmed nor refuted as a PALB2 pathogenicity mechanism and that PALB2 is not considered to have repetitive regions without known function. This frameshift variant is not an in-frame loss and cannot qualify for BP3.

VCEP rule
Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function
Evidence considered
  • PALB2 VCEP CSPEC BP3 entry: applicability is Not applicable; instructions state that small in-frame losses are neither confirmed nor refuted as a PALB2 pathogenicity mechanism and PALB2 is not considered to have repetitive regions without known function.
Sources
cspec ↗
BP4 N/ANot applicable: c.1592del is a truncating frameshift, so SpliceAI max delta 0.029 cannot establish BP4's no-impact conclusion. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP4 splicing path concerns absence of predicted splice impact, but NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)). For a frameshift, a no-splice-impact result does not negate the truncating protein effect and cannot support BP4; therefore BP4 is not applicable. The available SpliceAI max delta of 0.029 is not used for BP4.

VCEP rule
* Missense: Do not use. * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
  • SpliceAI max delta score = 0.029; this result is not used for BP4 because absence of predicted splice impact does not negate the frameshift protein effect.
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP explicitly instructs that BP5 should not be used for this disorder. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP5 not applicable and instructs not to use it because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2's moderate penetrance makes co-occurrence with other pathogenic variants more frequent.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • ClinGen PALB2 VCEP BP5 instruction: do not use because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference and PALB2 has moderate penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 VCEP explicitly states that BP6 is not for use. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen PALB2 VCEP BP6 instruction: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: c.1592del is an exonic frameshift, whereas BP7 is limited to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP7 rule is limited to synonymous variants and deep intronic variants beyond the specified donor and acceptor boundaries, with an RNA path for silent and intronic variants. NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)), so BP7 is outside its governing scope.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.1592del
Protein (HGVS p.)
NP_078951.2:p.(Leu531CysfsTer30)
GRCh38
chr16:23634953 CA>C
GRCh37
chr16:23646274 CA>C
Location and type
Exon 4 · frameshift
ClinVar
2673906, 126609, 2674131

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 v4.1 116 / 1,613,984 alleles AF 7.19e-05 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 49 / 282,888 alleles AF 0.000173 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 7.2e-05 · 116 / 1,613,984 alleles · 0 hom · FAF 6.8e-07
European (Finnish)112 / 64,008 0.0017
Remaining individuals1 / 62,488 1.6e-05
European (non-Finnish)3 / 1,180,040 2.5e-06
0 alternate alleles recorded in 7 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0.00017 · 49 / 282,888 alleles · 0 hom
European (Finnish)47 / 25,120 0.0019
Remaining individuals1 / 7,226 0.00014
European (non-Finnish)1 / 129,196 7.7e-06
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 7.18718e-05; MAF= 0.00719%, 116/1613984 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00174978; MAF= 0.17498%, 112/64008 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000173213; MAF= 0.01732%, 49/282888 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00187102; MAF= 0.18710%, 47/25120 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -471 bp
0.001
SpliceAI acceptor gainat -30 bp
0.005
SpliceAI donor lossat -91 bp
0.029
SpliceAI donor gainat +68 bp
0.001
Pangolin splice lossmagnitude shown
-0.117
Pangolin splice gain
0.012

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: c.1592del is an exonic frameshift, outside PP3's VCEP scope for silent, missense/in-frame, or qualifying intronic variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PP3 splicing path covers silent, missense/in-frame, and intronic variants outside donor and acceptor sites, while NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)); therefore PP3 is outside its governing scope. The available SpliceAI max delta of 0.029 is not used because this variant type is not covered by the PP3 rule.

VCEP rule
* Missense: Do not use. * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
  • SpliceAI max delta score = 0.029; this score is not evidence for PP3 because the VCEP PP3 splicing rule does not cover exonic frameshift variants.
Sources
cspec ↗
BP4 N/ANot applicable: c.1592del is a truncating frameshift, so SpliceAI max delta 0.029 cannot establish BP4's no-impact conclusion. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP4 splicing path concerns absence of predicted splice impact, but NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)). For a frameshift, a no-splice-impact result does not negate the truncating protein effect and cannot support BP4; therefore BP4 is not applicable. The available SpliceAI max delta of 0.029 is not used for BP4.

VCEP rule
* Missense: Do not use. * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
  • SpliceAI max delta score = 0.029; this result is not used for BP4 because absence of predicted splice impact does not negate the frameshift protein effect.
Sources
cspec ↗
BP7 N/ANot applicable: c.1592del is an exonic frameshift, whereas BP7 is limited to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP7 rule is limited to synonymous variants and deep intronic variants beyond the specified donor and acceptor boundaries, with an RNA path for silent and intronic variants. NM_024675.4:c.1592del is an exonic frameshift (p.(Leu531CysfsTer30)), so BP7 is outside its governing scope.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Variant: NM_024675.4:c.1592del, an exonic frameshift predicted as NP_078951.2:p.(Leu531CysfsTer30).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

8 paper records listed. 3 cited in the classification.

Cited in the classification

  • A recurrent mutation in PALB2 in Finnish cancer families.
    Erkko H et al. · 2007 Mar 15
    This paper reports the exact PALB2 c.1592delT allele in Finnish cancer families. It describes one multigenerational prostate-cancer family in which the truncation allele segregated; the family pedigree includes genotyped carriers and noncarriers, and all but one male carrier developed prostate cancer by age 76. It also states that segregation analysis in three breast-cancer families was attempted but was not sufficiently informative because suitable family-member DNA was unavailable.
    → PS4 · strong Names this variant
    PMID 17287723 ↗
    Source detail
    In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed.

    Location Abstract, lines 11-12; Figure 3 and Figure 3 caption

    Context Finnish familial and unselected cancer cohorts; germline mutation screening, family genotyping, pedigree analysis, and a prostate-cancer-family segregation observation.

  • Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
    The paper explicitly mentions the exact founder allele as PALB2 L531fs (c.1592delT), identifying it as a truncating mutation associated with increased breast-cancer risk.
    → PVS1 · very strong Names this variant
    PMID 18053174 ↗
    Source detail
    Until now, eight distinct truncating mutations have been associated with an increased risk for breast cancer (I76fs, L531fs, G796X, T841fs, A995fs, W1038X, N1039fs, and Y1183X) [9,10,12,13]. L531fs (c.1592delT) is a founder mutation in Finland but so far has not been seen outside of Finland.

    Location Discussion, paragraph beginning "PALB2 is a protein of approximately 130 kDa"

    Context Discussion of previously reported truncating PALB2 mutations; the study's new analyses focused on Q775X and two missense variants in French-Canadian breast-cancer cases and newborn controls.

  • Penetrance analysis of the PALB2 c.1592delT founder mutation.
    Erkko H et al. · 2008 Jul 15
    This paper studies the exact PALB2 c.1592delT founder mutation using 17 Finnish breast-cancer probands, their available relatives, pedigree data, and modified maximum-likelihood segregation analyses. It estimates a breast-cancer hazard ratio of 6.1 (95% CI, 2.2-17.2; P=0.01) and a 40% risk by age 70, but it does not report the LOD or Bayes factor required by the PALB2 VCEP PP1 or BS4 specifications.
    → PS4 · strong Names this variant
    PMID 18628482 ↗
    Source detail
    Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history.

    Location Abstract, Experimental Design; Methods, lines 186-208; Results, lines 288-299

    Context Seventeen Finnish PALB2 c.1592delT carrier probands and available relatives; direct sequencing, pedigree construction, modified Elston-Stewart maximum-likelihood segregation analysis, and Finnish cancer-incidence rates.

Other recorded publications

  • A novel PALB2 truncating mutation in an Italian family with male breast cancer.
    No paper-specific finding is recorded.
    PMID 25529982 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 28779002 ↗
  • 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 ↗

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

gnomAD v4.1 116 / 1,613,984 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.029 Open source ↗
ClinVar 14 Pathogenic · 1 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= 7.18718e-05; MAF= 0.00719%, 116/1613984 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00174978; MAF= 0.17498%, 112/64008 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000173213; MAF= 0.01732%, 49/282888 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00187102; MAF= 0.18710%, 47/25120 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 126609)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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.