The PALB2 NM_024675.4:c.3113G>A (NP_078951.2:p.(Trp1038Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV104552889, n = 2 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen; ClinVar ID 126711).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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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.
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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.
Met, very strong: p.Trp1038Ter is upstream of c.3301 and exon 10 skipping removes sequence from PALB2's indispensable WD40 domain.
PS4Strong
PS4 · strong
Met, Strong: exact-variant case-control data reported HR 30.1, 95% CI 7.5–120, and P<0.0001, satisfying the VCEP PS4 thresholds.
PM5Supporting
PM5 · supporting
Met, Supporting: p.Trp1038Ter is an NMD-prone truncation upstream of p.His1184, satisfying the PALB2 VCEP PM5_Supporting rule.
PP5Supporting
PP5 · supporting
Not applicable: the PALB2 VCEP explicitly prohibits use of PP5 for this VCEP.
Benign criteria applied · 1
BS1Strong
BS1 · strong
Met at strong: gnomAD v4.1 grpmax FAF is 0.025238%, exceeding the PALB2 VCEP BS1 threshold of >0.01%.
Recorded classification: Uncertain significance
VUS: PVS1 (very strong) and PS4 (strong) satisfy the VCEP pathogenic rule, while BS1 (strong) satisfies its likely-benign rule, creating conflicting evidence.
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
334 / 1,602,804 alleles
gnomAD v4.1: 334 / 1,602,804 alleles. Recorded AF 0.000208385. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.3, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 2 not met · 4 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Within the requested consequence criteria, PVS1 is met at very strong strength; PM4 and BP3 are not applicable under PALB2 VCEP v1.3.
The five requested criteria were adjudicated only under the PALB2 Version 1.3 VCEP specification and its governing PS1/PVS1 files.
PM5_Supporting is met because the variant is a truncating nonsense change at residue 1038, upstream of the VCEP cutoff p.His1184, while PS1, PM1, PP2, and BP1 are not applicable under their PALB2-specific rules.
PS2 and PM6 are not applicable under the PALB2 VCEP de novo policy.
PP1 cannot be assigned a strength without the VCEP-required quantitative AD co-segregation LOD or Bayes factor.
BS4 cannot be assessed because no quantitative non-segregation result meeting a VCEP threshold is available.
PS4 is met at Strong strength from an exact-variant population-based case-control comparison whose published hazard ratio, confidence interval, and p-value satisfy the PALB2 VCEP rule. PP4, PP5, BP5, and BP6 are not applicable because the VCEP explicitly excludes them for this framework or disease context.
All three requested computational-evidence criteria are outside their PALB2 VCEP-defined variant-type scopes for this nonsense substitution; no computational predictor is assigned to PP3, BP4, or BP7.
No criteria match.
Met · 5
PVS1Very strongVCEPMet, very strong: p.Trp1038Ter is upstream of c.3301 and exon 10 skipping removes sequence from PALB2's indispensable WD40 domain.
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Reasoning
NM_024675.4:c.3113G>A is a nonsense variant encoding NP_078951.2:p.(Trp1038Ter), in the clinically relevant PALB2 transcript. The stop codon is upstream of c.3301/p.Leu1101 and therefore falls within the VCEP's NMD-prone nonsense/frameshift region. Variant-specific RNA evidence additionally shows exon 10 skipping, producing an in-frame p.Gly1000_Gly1038del transcript that removes sequence from the indispensable WD40 domain (residues 856-1186), while the alternate 31-bp exon 10 deletion transcript is susceptible to NMD. The VCEP permits full PVS1 for NMD-escaping alterations adversely affecting WD40. The three requested notations were searched in PALB2_PVS1_v1.3.pdf.txt and no exact row for this variant was found; the call therefore follows the governing decision-tree rules rather than a pre-assigned row.
VCEP rule
Nonsense or frameshift | Predicted to undergo NMD (introduction of a premature termination codon between p.Asp2 and Leu1101/upstream of c.3301) | PVS1 ... PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1_Strong as the recommended baseline (Tayoun 2018 PMID 30192042).
Evidence considered
Case normalization identifies NM_024675.4:c.3113G>A as NP_078951.2:p.(Trp1038Ter), also p.(W1038*).
PALB2_PVS1_v1.3.pdf.txt, page 4 decision-tree row: nonsense or frameshift predicted to undergo NMD, with a premature termination codon between p.Asp2 and Leu1101/upstream of c.3301, receives PVS1.
PMID:23448497, Results section 'PALB2 c.3113G>A' and Table 3a: RT-PCR showed exon 10 deletion r.2997_3113del, p.Gly1000_Gly1038del, and a 31-bp exon 10 deletion causing p.Gly1028fs*3; the latter appeared susceptible to nonsense-mediated decay, whereas the exon-10-deleted transcript did not undergo extensive nonsense-mediated decay.
PALB2_PVS1_v1.3.pdf.txt, page 1: the WD40 domain spans residues 856-1186 and is considered indispensable for PALB2 protein function; page 3 states that NMD-escaping alterations adversely affecting WD40 can receive PVS1.
The variant is in exon 10 of the clinically relevant 13-exon transcript and the observed exon-10-deleted product removes residues within the VCEP-defined WD40 domain.
Still missing
PALB2_PVS1_v1.3.pdf.txt was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*; no exact entry for this variant was found.
PS4StrongVCEPMet, Strong: exact-variant case-control data reported HR 30.1, 95% CI 7.5–120, and P<0.0001, satisfying the VCEP PS4 thresholds.
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Reasoning
The PALB2 VCEP PS4 rule requires a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥3 or a lower 95% CI ≥1.5. PMID:21182766 explicitly verified the exact variant c.3113G>A/W1038X in 5 of 1,403 population-based breast-cancer cases and 0 of 764 unaffected controls, reporting hazard ratio 30.1 (95% CI 7.5–120; P<0.0001). This is a case-control comparison and meets p≤.05, HR≥3, and lower 95% CI≥1.5. As an additional count-based check, PMID:28779002 reported 20/13,087 cases versus 1/5,488 controls; the computed OR is 8.40 (95% CI 1.13–62.59, uncorrected Woolf calculation), while its grouped C-terminal-variant analysis reported OR 3.57 (95% CI 1.27–10.1; p=0.016) and was not used as the primary exact-variant threshold basis. The exact-variant evidence from PMID:21182766 independently satisfies the VCEP PS4 Strong rule.
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 Version 1.3 PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥3 or lower 95% CI ≥1.5).
PMID:21182766, exact variant c.3113G>A/W1038X: 5 of 1,403 population-based breast-cancer case probands versus 0 of 764 unaffected controls; published hazard ratio 30.1, 95% CI 7.5–120, P<0.0001. This is a case-control comparison; the published HR and CI meet the VCEP thresholds.
PMID:28779002, exact variant c.3113G>A/p.Trp1038Ter: 20 cases and 1 control in a population-based case-control study of 13,087 cases and 5,488 controls. OR computed from counts as (20/13,067)/(1/5,487)=8.40; 95% CI computed by the Woolf method = 1.13–62.59.
PMID:23448497 verified the exact variant in eight affected women from 747 multiple-case breast-cancer families; this is case-series evidence and was not substituted for the VCEP case-control requirement.
PMID:18053174 verified the exact protein-level equivalent W1038X in two families but supplied no case-control metric, so it was not used as the threshold basis.
The literature_pass PS4 leads for PMID:21182766, PMID:23448497, PMID:23471749, and PMID:27595995 were checked against their provided abstracts/full-text extracts; the decisive PS4 assignment rests on the independently verified case-control evidence from PMID:21182766.
PM5SupportingVCEPMet, Supporting: p.Trp1038Ter is an NMD-prone truncation upstream of p.His1184, satisfying the PALB2 VCEP PM5_Supporting rule.
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Reasoning
PM5 is met at Supporting strength. The PALB2 VCEP defines PM5_Supporting for DNA variants as all NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.His1184. This variant is a nonsense truncation at p.Trp1038Ter, well upstream of p.His1184, and the PALB2 VCEP recognizes nonsense variants as null variants in a gene with an established loss-of-function mechanism; therefore it meets the specified PM5 route. The VCEP instructions also state that PM5 is Supporting rather than Moderate and anchor the cutoff to the most C-terminal known pathogenic variant, p.Tyr1183*.
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
Evidence considered
PALB2 CSPEC PM5 rule: DNA variants qualify when they are NMD-prone truncating variants with PVS1 at Very Strong and a premature termination codon upstream of p.His1184; the specified strength is Supporting.
Variant facts: NM_024675.4:c.3113G>A is a nonsense variant producing NP_078951.2:p.(Trp1038Ter), so the termination codon is at residue 1038, upstream of His1184.
PALB2 PVS1 guide: nonsense variants are null variants, and PALB2 loss of function is an established disease mechanism in the VCEP framework.
PALB2 VCEP PM5 instructions identify p.Tyr1183* as the most C-terminal known pathogenic variant and specify PM5_Supporting rather than PM5_Moderate.
PP5SupportingVCEPNot applicable: the PALB2 VCEP explicitly prohibits use of PP5 for this VCEP.
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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 Version 1.3 PP5 entry: applicability = not applicable for this VCEP; the criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.
BS1StrongVCEPMet at strong: gnomAD v4.1 grpmax FAF is 0.025238%, exceeding the PALB2 VCEP BS1 threshold of >0.01%.
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Reasoning
The PALB2 VCEP defines BS1 Strong as Grpmax Filtering AF >0.01% in gnomAD. The gnomAD v4.1 all-comers grpmax FAF is 0.00025238 (0.025238%), which exceeds 0.01%. The result meets BS1 at Strong strength.
VCEP rule
Grpmax Filtering AF **>.01%** in gnomAD
Evidence considered
gnomAD v4.1 all-comers: grpmax FAF 0.00025238 (0.025238%); this exceeds the VCEP BS1 threshold of 0.0001 (0.01%).
PM2VCEPNot met: the highest gnomAD v4.1 subpopulation AF is 0.027778%, above the PALB2 VCEP PM2 threshold of ≤0.000333%.
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Reasoning
The PALB2 VCEP applies PM2 Supporting when the frequency is ≤1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with a single-observation exception. In gnomAD v4.1 the highest subpopulation AF is 0.000277778 (0.027778%; 325/1,170,000 alleles), far above 0.000333%; gnomAD v2.1 is likewise above the threshold at 0.000120154 (0.012015%). The single-observation exception does not apply because the v4.1 highest-frequency subpopulation has 325 alternate alleles.
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
gnomAD v4.1 all-comers highest subpopulation: European non-Finnish AF 0.000277778 (0.027778%), 325/1,170,000 alleles, homozygotes 0.
gnomAD v2.1 all-comers highest subpopulation: African/African American AF 0.000120154 (0.012015%), 3/24,968 alleles, homozygotes 0.
The PM2 single-observation exception is inapplicable because the highest-frequency v4.1 subpopulation has 325 alternate alleles, not n=1.
BA1VCEPNot met: gnomAD v4.1 grpmax FAF is 0.025238%, below the PALB2 VCEP BA1 threshold of >0.1%.
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Reasoning
The PALB2 VCEP defines BA1 as Grpmax Filtering AF >0.1% in gnomAD. The highest available all-comers grpmax FAF is 0.00025238 in gnomAD v4.1 (0.025238%), below 0.1%; gnomAD v2.1 is also below the threshold at 0.00006665 (0.006665%). Therefore BA1 is not met.
VCEP rule
Grpmax Filtering AF **>.1%** in gnomAD
Evidence considered
gnomAD v4.1 all-comers: grpmax FAF 0.00025238 (0.025238%), with highest subpopulation AF 0.000277778 (0.027778%) in European non-Finnish individuals.
PM3VCEPNot assessed: no Fanconi Anemia PM3-table entry or documented pathogenic variant in trans is available to establish a VCEP PM3 point total.
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Reasoning
The PALB2 VCEP PM3 rule is for a recessive disorder when the variant is detected in trans with a pathogenic variant, using the Fanconi Anemia PM3 tables and their point assignments. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*, and no variant-specific table entry was found. The available exact-variant literature reports breast-cancer observations, not a PALB2-related Fanconi Anemia proband with documented phase and a classified pathogenic/likely pathogenic variant in trans; therefore the VCEP PM3 point total cannot be determined and PM3 is not assessed.
VCEP rule
PM3
Evidence considered
PALB2_PM3_BS2_1.3.pdf, Fanconi Anemia PM3 table: no row matching c.3113G>A, p.Trp1038Ter, or p.W1038*.
PMID:21182766 reports five breast-cancer case probands with PALB2 c.3113G>A/W1038X and family segregation, but does not document Fanconi Anemia or a pathogenic variant in trans.
PMID:23448497 reports c.3113G>A in eight affected women and altered splicing, but does not document Fanconi Anemia or phase with a pathogenic/likely pathogenic variant.
Still missing
PALB2_PM3_BS2_1.3.pdf was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*; no entry for this variant was found.
No documented PALB2-related Fanconi Anemia proband with confirmed phase and a VCEP-classified pathogenic/likely pathogenic variant in trans was available.
PP1VCEPNot assessed: segregation occurred in two families, but no quantitative LOD or Bayes factor is available to meet the VCEP's PP1 thresholds.
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Reasoning
The exact variant was reported to segregate with breast cancer in both of two early-onset carrier families based on predictive testing. However, the PALB2 VCEP mandates quantitative co-segregation analysis for more accurate assessment and requires an AD LOD or Bayes factor threshold: supporting LOD ≥0.3 or LR ≥2:1, moderate LOD ≥0.60 or LR ≥4:1, or strong LOD ≥1.26 or LR ≥18:1. No LOD or Bayes factor is provided, so a PP1 strength cannot be assigned.
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
Casadei et al. (PMID:21182766) explicitly studied PALB2 c.3113G>A/W1038X and reported that the variant segregated with breast cancer in both early-onset carrier families based on predictive testing.
The same paper described five population-based carrier families and eight additional carrier families from 779 multiple-case families, but did not provide a PALB2 VCEP-compatible quantitative LOD or Bayes factor for this variant.
The VCEP PP1 rule requires quantitative co-segregation analysis and uses AD thresholds of LOD ≥0.3 or LR ≥2:1 for supporting, LOD ≥0.60 or LR ≥4:1 for moderate, and LOD ≥1.26 or LR ≥18:1 for strong.
Still missing
Quantitative PALB2 autosomal-dominant co-segregation result (LOD or Bayes factor/LR) is not available.
BS2VCEPNot assessed: the governing BS2 table has no c.3113G>A/p.Trp1038Ter/p.W1038* row, and available controls are from a prohibited population-based cohort.
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Reasoning
The PALB2 VCEP directs BS2 assessment to its Fanconi Anemia BS2 tables and prohibits use of population-based cohorts such as gnomAD. The required file PALB2_PM3_BS2_1.3.pdf was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*, with no matching row found. The available PMID:21182766 observation is from a population-based control cohort, not an eligible clinical or research-cohort healthy adult observation under the table rules. No qualifying BS2 point assignment is therefore 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.
Evidence considered
PALB2_PM3_BS2_1.3.pdf.txt was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*; no matching entry was found.
The VCEP BS2 text states: Do not use for individuals in population based cohorts, such as gnomAD; the table footnote limits homozygote scoring to phenotyped individuals from clinical or research cohorts and excludes frequency-code data.
PMID:21182766 reports no carriers among 764 population-based unaffected controls; this is a population-based control observation and does not satisfy the VCEP BS2 cohort requirement.
Still missing
No entry for c.3113G>A, p.Trp1038Ter, or p.W1038* was found in PALB2_PM3_BS2_1.3.pdf.txt.
No eligible clinical or research-cohort healthy-adult BS2 observation with sufficient age, zygosity, phase, and phenotype details was identified.
BS4VCEPNot assessed: no non-segregation LOD or Bayes factor is available to meet the VCEP's BS4 thresholds.
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Reasoning
The available variant-specific evidence reports segregation with breast cancer in two early-onset families and does not report non-segregation in affected relatives or an aggregate quantitative non-segregation result. The PALB2 VCEP requires BS4 quantitative thresholds of supporting LOD ≤−0.32 or LR ≤0.48, moderate LOD ≤−0.64 or LR ≤0.23, or strong LOD ≤−1.28 or LR ≤0.053:1; none is available.
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
Casadei et al. (PMID:21182766) reported segregation with breast cancer in both early-onset carrier families but did not provide a quantitative non-segregation LOD or Bayes factor for this variant.
The VCEP BS4 thresholds are supporting LOD ≤−0.32 or LR ≤0.48, moderate LOD ≤−0.64 or LR ≤0.23, and strong LOD ≤−1.28 or LR ≤0.053:1; the available evidence does not establish any of these thresholds.
Still missing
Quantitative PALB2 co-segregation/non-segregation result (LOD or Bayes factor/LR) is not available.
Not applicable · 17· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: PALB2 PS1 is restricted to comparable splice defects, whereas c.3113G>A produces the nonsense variant p.Trp1038Ter.
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Reasoning
PS1 is not applicable. The PALB2 PS1 guide excludes missense use and routes only splicing variants with similar predicted or observed splice defects to the PS1 splicing table. This variant is a nonsense change, NP_078951.2:p.(Trp1038Ter), not a splice variant. All requested notations were searched in PALB2_PS1_1.3.pdf.txt; no entry for c.3113G>A, p.Trp1038Ter, or p.W1038* was found.
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. (PMID: 36865205)
Evidence considered
PALB2 PS1 guide: the missense route says not to use PS1, and the splicing route directs comparable splicing variants to the PALB2 PS1 Splicing table.
Variant normalization: NM_024675.4:c.3113G>A is NP_078951.2:p.(Trp1038Ter), a nonsense variant.
The governing PS1 file was searched for c.3113G>A, p.Trp1038Ter, and p.W1038*; no matching row was found.
Still missing
No entry for c.3113G>A, p.Trp1038Ter, or p.W1038* was found in PALB2_PS1_1.3.pdf.txt.
PS2VCEPNot applicable: the PALB2 VCEP states that informative de novo occurrences have not been observed for autosomal-dominant disease.
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Reasoning
The PALB2 VCEP marks PS2 not applicable 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 recessive 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 and de novo AR conditions are unlikely to be informed by phase
Evidence considered
The PALB2 VCEP CSPEC entry marks PS2 not applicable and states that informative de novo occurrences have not yet been observed for autosomal-dominant disease.
PS3VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly marks PS3 as "Not applicable".
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Reasoning
PS3 is not applicable under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP PALB2 Version 1.3 specification. The VCEP entry for PS3 explicitly marks applicability as "Not applicable", so no functional assay evidence can be assigned as PS3 under this governing framework.
VCEP rule
Not applicable
Evidence considered
ClinGen PALB2 VCEP Version 1.3 CSPEC PS3 entry: applicability = "Not applicable"; protein and RNA assay instructions do not authorize PS3 use under this specification.
PM1VCEPNot applicable: the PALB2 VCEP excludes PM1 because missense pathogenic variation is not yet a confirmed disease mechanism.
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Reasoning
PM1 is not applicable under the PALB2 VCEP specification because the VCEP explicitly states that missense pathogenic variation in PALB2 is not yet a confirmed disease mechanism. The variant is a nonsense change at codon 1038, and vcep_materials.json contains no domain_tables entry for PALB2; no separate VCEP-approved PM1 domain or hotspot route is available for this criterion.
VCEP rule
Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
Evidence considered
PALB2 CSPEC PM1 instructions: do not use because missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
vcep_materials.json domain_tables is empty for PALB2, so there is no authoritative domain-table residue route to evaluate.
Variant normalization identifies p.(Trp1038Ter), a nonsense change rather than a missense change.
PM4VCEPNot applicable: the VCEP restricts PM4 to stop-loss variants, whereas c.3113G>A is a stop-gain nonsense variant.
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Reasoning
The PALB2 VCEP marks PM4 not applicable and instructs that it is used for stop-loss variants only. This variant is a nonsense/stop-gain variant, not a stop-loss variant.
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 PM4 entry in vcep_materials.json/prefetch.json: applicability is Not applicable and instructions state, 'Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.'
The case consequence is nonsense/stop-gain p.Trp1038Ter, not stop-loss.
PM6VCEPNot applicable: the PALB2 VCEP says informative de novo occurrences have not been observed for PALB2 autosomal-dominant or autosomal-recessive disease.
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Reasoning
The PALB2 VCEP marks PM6 not applicable for autosomal-dominant and autosomal-recessive disease because informative de novo occurrences have not been observed and de novo recessive conditions are unlikely to be informed by phase.
VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
The PALB2 VCEP CSPEC entry marks PM6 not applicable and states that informative de novo occurrences have not yet been observed.
PP2VCEPNot applicable: PALB2 PP2 is prohibited by the VCEP and the variant is nonsense, not missense.
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Reasoning
PP2 is not applicable. The PALB2 VCEP explicitly says not to use PP2 because missense is not yet confirmed or refuted as a disease mechanism, and this variant is nonsense rather than missense.
VCEP rule
Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2
Evidence considered
PALB2 CSPEC PP2 instructions: do not use because missense is not yet confirmed or refuted as a mechanism of disease for PALB2.
Variant normalization identifies p.(Trp1038Ter), a nonsense variant.
PP3N/ANot applicable: the PALB2 VCEP PP3 splicing rule covers silent, missense/in-frame, and specified intronic variants, not nonsense variants.
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Reasoning
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter). The PALB2 VCEP PP3 rule limits its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor sites; it does not include nonsense variants. Therefore PP3 is not_applicable before considering the available SpliceAI result.
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 normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP PP3 rule's splicing scope is limited to silent, missense/in-frame, and intronic variants outside donor and acceptor sites; a nonsense substitution is outside that scope, so the SpliceAI score is not used for PP3.
PP4VCEPNot applicable: the PALB2 VCEP excludes PP4 for hereditary breast cancer because genetic heterogeneity prevents specific phenotype discrimination.
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Reasoning
The PALB2 VCEP marks PP4 as not applicable for autosomal dominant disease because breast cancer has genetic heterogeneity and no features readily distinguish hereditary from sporadic causes. This PALB2 cancer-predisposition interpretation is governed by the autosomal dominant PP4 restriction, so phenotype-specific PP4 cannot be assigned.
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 Version 1.3 PP4 entry: the autosomal dominant breast-cancer phenotype is genetically heterogeneous and lacks features that readily distinguish hereditary from sporadic disease.
BS3VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly marks BS3 as "Not applicable".
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Reasoning
BS3 is not applicable under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP PALB2 Version 1.3 specification. The VCEP entry for BS3 explicitly marks applicability as "Not applicable", so no functional assay evidence can be assigned as BS3 under this governing framework.
VCEP rule
Not applicable
Evidence considered
ClinGen PALB2 VCEP Version 1.3 CSPEC BS3 entry: applicability = "Not applicable"; protein and RNA assay instructions do not authorize BS3 use under this specification.
BP1N/ANot applicable: BP1 applies to missense variants, but c.3113G>A produces the nonsense variant p.Trp1038Ter.
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Reasoning
BP1 is not applicable because the PALB2 VCEP limits it to missense variants, whereas NM_024675.4:c.3113G>A is a nonsense variant producing p.Trp1038Ter.
VCEP rule
Apply to all missense variants.
Evidence considered
PALB2 CSPEC BP1 rule: apply BP1 to all missense variants.
Variant normalization identifies p.(Trp1038Ter), a nonsense variant rather than a missense variant.
BP3VCEPNot applicable: the VCEP excludes BP3 because PALB2 lacks repetitive regions without known function, and this variant is a nonsense stop-gain.
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Reasoning
The PALB2 VCEP marks BP3 not applicable and states that PALB2 is not considered to have repetitive regions without known function. This nonsense variant is not a small in-frame loss in such a region.
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 BP3 entry in vcep_materials.json/prefetch.json: applicability is Not applicable and instructions state, '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'.
The case consequence is nonsense/stop-gain p.Trp1038Ter rather than a small in-frame insertion or deletion.
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter). The PALB2 VCEP BP4 rule applies its no-predicted-splicing-impact path to splicing variants and expressly excludes missense variants; the requested scope also excludes nonsense variants because a negative splice prediction does not negate the truncating protein effect. BP4 is therefore not_applicable without using the available SpliceAI score.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
Variant normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP BP4 rule specifies no predicted impact via splicing for splicing variants and says not to apply it for missense variants; under the criterion scope, BP4 is also not applicable to a nonsense variant because no splice-impact prediction removes its truncating protein effect.
BP5VCEPNot applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants are expected and may not alter phenotype.
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Reasoning
The PALB2 VCEP marks BP5 as not applicable and instructs that it should not be used because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2 has moderate penetrance. No alternate molecular basis can override this VCEP prohibition.
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 Version 1.3 BP5 entry: cases with multiple pathogenic variants have been observed without a noticeable phenotype difference, and PALB2 moderate penetrance makes co-occurrence more frequent.
BP6VCEPNot applicable: the PALB2 VCEP explicitly prohibits use of BP6 for this VCEP.
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Reasoning
The PALB2 VCEP marks BP6 as not applicable and instructs that the criterion is not for use. Reports from reputable sources describing the variant as benign therefore cannot be assigned as BP6 under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ClinGen PALB2 VCEP Version 1.3 BP6 entry: applicability = not applicable for this VCEP; the criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.
BP7N/ANot applicable: BP7 is restricted to synonymous or deep intronic variants, whereas this variant is a nonsense substitution.
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Reasoning
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter), not a synonymous or deep intronic variant. The PALB2 VCEP BP7 rule is limited to synonymous and deep intronic variants, with an optional RNA path for silent substitutions and intronic variants. This nonsense variant is outside BP7 scope, so BP7 is not_applicable.
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 normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP BP7 rule applies to synonymous and deep intronic variants, and its RNA path applies to silent substitutions and intronic variants; a nonsense substitution is outside both paths.
AF 0.00021 · 334 / 1,602,804 alleles · 0 hom · FAF 0.00025
European (non-Finnish)325 / 1,170,000
0.00028
African/African American5 / 74,618
6.7e-05
Remaining individuals4 / 62,120
6.4e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 6e-05 · 17 / 282,756 alleles · 0 hom · FAF 6.7e-05
African/African American3 / 24,968
0.00012
European (non-Finnish)14 / 129,120
0.00011
0 alternate alleles recorded in 6 other groups: 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= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +116 bp
0.629
SpliceAI acceptor gainat +460 bp
0.002
SpliceAI donor lossat +0 bp
0.742
SpliceAI donor gainat +31 bp
0.170
Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.001
Other predictors
REVEL
Not available
BayesDel
0.630
How the predictions were used
PP3N/ANot applicable: the PALB2 VCEP PP3 splicing rule covers silent, missense/in-frame, and specified intronic variants, not nonsense variants.
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Reasoning
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter). The PALB2 VCEP PP3 rule limits its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor sites; it does not include nonsense variants. Therefore PP3 is not_applicable before considering the available SpliceAI result.
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 normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP PP3 rule's splicing scope is limited to silent, missense/in-frame, and intronic variants outside donor and acceptor sites; a nonsense substitution is outside that scope, so the SpliceAI score is not used for PP3.
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter). The PALB2 VCEP BP4 rule applies its no-predicted-splicing-impact path to splicing variants and expressly excludes missense variants; the requested scope also excludes nonsense variants because a negative splice prediction does not negate the truncating protein effect. BP4 is therefore not_applicable without using the available SpliceAI score.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
Variant normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP BP4 rule specifies no predicted impact via splicing for splicing variants and says not to apply it for missense variants; under the criterion scope, BP4 is also not applicable to a nonsense variant because no splice-impact prediction removes its truncating protein effect.
BP7N/ANot applicable: BP7 is restricted to synonymous or deep intronic variants, whereas this variant is a nonsense substitution.
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Reasoning
The variant is a nonsense substitution, NM_024675.4:c.3113G>A (p.Trp1038Ter), not a synonymous or deep intronic variant. The PALB2 VCEP BP7 rule is limited to synonymous and deep intronic variants, with an optional RNA path for silent substitutions and intronic variants. This nonsense variant is outside BP7 scope, so BP7 is not_applicable.
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 normalization: NM_024675.4:c.3113G>A produces NP_078951.2:p.(Trp1038Ter), a nonsense substitution.
The VCEP BP7 rule applies to synonymous and deep intronic variants, and its RNA path applies to silent substitutions and intronic variants; a nonsense substitution is outside both paths.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.74). BayesDel score = 0.63.
8 paper records listed. 4 cited in the classification.
Cited in the classification
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
The paper lists W1038X, the protein-level equivalent of PALB2 c.3113G>A/p.W1038*, as having been found in two separate families, but gives no case-control counts or threshold-bearing association estimate.
Context Discussion of prior PALB2 breast-cancer studies; no variant-specific case-control methodology or population-frequency details were provided for W1038X.
A PALB2 mutation associated with high risk of breast cancer.
Southey MC et al. · 2010
The paper explicitly studied PALB2 c.3113G>A, reported as W1038X, and found five independent population-based breast cancer case probands. The two early-onset probands had very strong breast cancer family histories, and predictive testing showed segregation with breast cancer in both families. No quantitative LOD or Bayes factor for this variant was reported.
Both of the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families.
Location Abstract, Results
Context Population-based Australian Breast Cancer Family Registry case cohort; high-resolution melting and sequencing for younger cases; TaqMan genotyping for cases aged 40–59 and unaffected controls; family predictive testing and segregation analysis; modified segregation analysis using first- and second-degree relatives.
Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families.
Teo ZL et al. · 2013 Feb 28
The paper explicitly reports PALB2 c.3113G>A, p.Trp1038* and variant-specific RNA findings. RT-PCR identified an exon-10-deleted transcript encoding p.Gly1000_Gly1038del that did not undergo extensive nonsense-mediated decay and a 31-bp exon 10 deletion causing p.Gly1028fs*3 that appeared susceptible to nonsense-mediated decay.
→ PVS1 · very strong→ PS4 · strongNames this variant
Context HRM screening and Sanger sequencing of 747 affected women from Australasian multiple-case breast cancer families; RT-PCR and Sanger sequencing of EBV-transformed lymphoblastoid cell-line transcripts, with and without cycloheximide treatment, to assess alternate splicing and nonsense-mediated decay.
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
The paper explicitly reports PALB2 c.3113G>A/p.Trp1038Ter in 20 breast-cancer cases and 1 control from a population-based case-control study. From the exact-variant counts, the computed OR is 8.40 with a Woolf 95% CI of 1.13–62.59.
Three variants, all in the final 280 codons of the gene, were more common: PALB2 c.2718G>A (p.Trp906Ter, rs180177122; seven cases, one control), c.3113G>A (p.Trp1038Ter, rs180177132; 20 cases, one control) and c.3116delA (p.Asn1039IlefsTer2, rs180177133; eight cases, one control)
Location Results, ‘BC risks associated with ATM, CHEK2 and PALB2 truncating variants’ paragraph; Table 1 and online supplementary table S5
Context Population-based case-control study of 13,087 breast-cancer cases and 5,488 controls from East Anglia, UK, using targeted sequencing of PALB2 and other DNA-repair genes.
Other recorded publications
A novel PALB2 truncating mutation in an Italian family with male breast cancer.
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= 0.000208385; MAF= 0.02084%, 334/1602804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000277778; MAF= 0.02778%, 325/1170000 alleles, homozygotes = 0); grpmax FAF= 0.00025238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01225e-05; MAF= 0.00601%, 17/282756 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120154; MAF= 0.01202%, 3/24968 alleles, homozygotes = 0); grpmax FAF= 6.665e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (35 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 = 126711)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.74). BayesDel score = 0.63.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104552889, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 11.0.14.
The current version is 11.0.18.
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