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PALB2c.1597A>GUncertain significance
Print report
Variant interpretation report

PALB2 c.1597A>G, p.Thr533Ala

NM_024675.4:c.1597A>G NP_078951.2:p.(Thr533Ala) Missense · exon 4 View identifiers
Classification
Uncertain significance

Variant description:

The PALB2 NM_024675.4:c.1597A>G (NP_078951.2:p.(Thr533Ala)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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

Uncertain.The recorded classification is uncertain significance.

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: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Supporting
BP1 · supporting

Met, Supporting: the PALB2 VCEP applies BP1 to all missense variants, including p.Thr533Ala.

Recorded classification: Uncertain significance

VUS: BP1 (supporting) was applied, but the PALB2 Version 1.3 VCEP combination rules satisfy neither a pathogenic nor a benign classification rule.

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
7 / 1,614,064 alleles

gnomAD v4.1: 7 / 1,614,064 alleles. Recorded AF 4.33688e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95267e-06; MAF= 0.00080%, 2/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.028 recorded score

Recorded REVEL score: 0.028. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
7 reported laboratory submissions

6 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.

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: 1 met · 4 not met · 5 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

Within this requested group, PS4 cannot be assessed because the available study is aggregate PALB2 case-control evidence without variant-specific statistics, while PP4, PP5, BP5, and BP6 are explicitly not applicable under the PALB2 VCEP rules.

PP3 is not met because the VCEP-named SpliceAI maximum delta score is 0.032, below the VCEP threshold of ≥0.2.

BP4 and BP7 are not applicable because the variant is an exonic missense substitution and lies outside each criterion's VCEP-defined scope.

Met · 1

BP1 SupportingVCEPMet, Supporting: the PALB2 VCEP applies BP1 to all missense variants, including p.Thr533Ala. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and the PALB2 VCEP BP1 rule applies BP1 at Supporting strength to all missense variants.

VCEP rule
Apply to all missense variants.
Evidence considered
  • PALB2 CSPEC BP1 rule: Supporting strength applies to all missense variants.
  • Variant assessment: NM_024675.4:c.1597A>G is a missense variant encoding p.Thr533Ala.
Sources
cspec ↗pvs1_variant_assessment

Not met · 4 · evaluated, threshold not reached

PM2 VCEPNot met: the highest gnomAD v2.1 non-cancer subpopulation AF is 0.00328%, above the VCEP PM2 threshold of 0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PM2 rule permits PM2 Supporting when the frequency is at most 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with an exception for a frequency above that value only when n=1 in a single subpopulation and absent from every other subpopulation. The governing non-cancer exome record, gnomAD v2.1 non-cancer, has highest subpopulation AF 3.27590e-05 (0.00328%), above 0.000333%, with the allele also observed in other subpopulations; therefore the single-subpopulation exception does not apply. gnomAD v4.1 likewise has highest subpopulation AF 1.09779e-05 (0.00110%), above the threshold.

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
  • ClinGen PALB2 v1.3 CSPEC PM2 rule: frequency <= 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; the exception requires n=1 in a single subpopulation and absence from every other subpopulation.
  • gnomAD v2.1 non-cancer exomes: total AF 8.4406e-06, 2/236,950 alleles, homozygotes = 0; highest subpopulation was South Asian at AF 3.27590e-05 (0.00328%), 1/30,526 alleles, and the variant was also observed in European non-Finnish and other subpopulations.
  • gnomAD v4.1: highest subpopulation was South Asian at AF 1.09779e-05 (0.00110%), 1/91,092 alleles; the variant was also observed in European non-Finnish individuals, so the single-subpopulation exception is not satisfied.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 VCEPNot met: SpliceAI maximum delta score is 0.032, below the VCEP PP3 threshold of ≥0.2 for predicted splice impact in missense variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP rule excludes the missense-protein path but permits PP3 for predicted splice impact in missense/in-frame variants. This variant is NM_024675.4:c.1597A>G, annotated as missense p.(Thr533Ala), and SpliceAI is the named predictor for this path. Its maximum delta score is 0.032, below the VCEP threshold of ≥0.2; therefore the VCEP PP3 splicing criterion is not met.

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
  • ClinGen PALB2 VCEP CSPEC PP3 rule: the missense path is excluded, while the splicing path applies to silent, missense/in-frame, and specified intronic variants using SpliceAI ≥0.2.
  • SpliceAI Lookup for NM_024675.4:c.1597A>G: DS_AG 0.001, DS_AL 0.032, DS_DG 0.000, DS_DL 0.004; maximum delta score 0.032. This is below the VCEP PP3 cutoff of ≥0.2.
Sources
cspec ↗spliceai ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.000183%, below the VCEP BA1 threshold of greater than 0.1%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BA1 rule requires a grpmax filtering allele frequency greater than 0.1% in gnomAD. gnomAD v4.1 reports grpmax FAF 1.83e-06, equivalent to 0.000183%, which is below 0.1%; therefore BA1 is not met. The gnomAD v2.1 all-comers and non-cancer exome datasets also do not provide a value approaching the BA1 threshold.

VCEP rule
Grpmax Filtering AF **>.1%** in gnomAD
Evidence considered
  • ClinGen PALB2 v1.3 CSPEC BA1 rule: Grpmax Filtering AF >0.1% in gnomAD.
  • gnomAD v4.1 record for PALB2 c.1597A>G / p.Thr533Ala: grpmax FAF = 1.83e-06 (0.000183%); total AF = 4.33688e-06, 7/1,614,064 alleles, homozygotes = 0.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.000183%, below the VCEP BS1 threshold of greater than 0.01%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BS1 rule requires a grpmax filtering allele frequency greater than 0.01% in gnomAD. gnomAD v4.1 reports grpmax FAF 1.83e-06, equivalent to 0.000183%, which is below 0.01%; therefore BS1 is not met. The highest gnomAD v4.1 subpopulation AF is 1.09779e-05 (0.00110%), also below the VCEP BS1 threshold.

VCEP rule
Grpmax Filtering AF **>.01%** in gnomAD
Evidence considered
  • ClinGen PALB2 v1.3 CSPEC BS1 rule: Grpmax Filtering AF >0.01% in gnomAD.
  • gnomAD v4.1 record for PALB2 c.1597A>G / p.Thr533Ala: grpmax FAF = 1.83e-06 (0.000183%); highest observed subpopulation was South Asian at AF 1.09779e-05 (0.00110%), 1/91,092 alleles, homozygotes = 0.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 VCEPNot assessed: the available case-control study analyzed PALB2 variants in aggregate and reported no variant-specific p-value, effect estimate, or confidence interval for c.1597A>G. Details ▾Hide ▴
Reasoning

The VCEP requires a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥3 or a lower 95% confidence interval ≥1.5. PMID:33471991 analyzed PALB2 variants in aggregate in 60,466 women with breast cancer and 53,461 controls, but it did not report NM_024675.4:c.1597A>G or provide variant-specific case-control counts, p-value, effect estimate, or confidence interval. Therefore the PS4 rule cannot be evaluated for this variant.

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 PS4 rule: case-control studies require p-value ≤.05 and odds ratio, hazard ratio, or relative risk ≥3, or lower 95% confidence interval ≥1.5.
  • Dorling et al., PMID:33471991, Breast Cancer Association Consortium analysis: 60,466 women with breast cancer and 53,461 controls; PALB2 truncating and rare missense variants were analyzed in aggregate, and c.1597A>G/p.(T533A) was not reported.
Still missing
  • Variant-specific case-control counts or an effect estimate with p-value and/or lower 95% confidence interval are unavailable.
Sources
cspec ↗PMID:33471991 ↗
PM3 VCEPNot assessed: no Fanconi Anemia proband, pathogenic variant in trans, or phase evidence was available to assign PALB2 VCEP PM3 points. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PM3 rule requires Fanconi Anemia evidence for the variant detected in trans with a pathogenic variant, with points assigned per unrelated proband. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.1597A>G, p.Thr533Ala, p.T533A, and the broader coordinate/protein strings 1597, 533, Thr533, and T533; no entry for this variant was found. The case evidence contains no affected Fanconi Anemia proband observation, pathogenic variant in trans or cis, homozygous observation in a clinical or research cohort, or phase information from which PM3 points could be assigned. Therefore PM3 cannot be assessed from the available VCEP-governed evidence.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant. Fanconi Anemia PM3 points are assigned per unrelated PALB2-related Fanconi Anemia proband, with 2.0 points for confirmed in trans or homozygote and 1.0 point when phase is unknown for a phenotype-consistent case; PM3 strength thresholds are Supporting 1.0, Moderate 2.0, Strong 4.0, and Very Strong 8.0 points.
Evidence considered
  • PALB2 VCEP CSPEC PM3 entry: PM3 is assigned from Fanconi Anemia PM3-table points, with Supporting = 1 point, Moderate = 2 points, Strong = at least 4 points, and Very Strong = at least 8 points.
  • ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP, PALB2 specification v1.3 - PM3/BS2 tables: searched c.1597A>G, p.Thr533Ala, p.T533A, 1597, 533, Thr533, and T533; no matching row or pre-assigned code was found.
  • The case evidence bundle contains no phase, Fanconi Anemia proband, pathogenic-variant co-occurrence, or clinical-cohort homozygote observation for NM_024675.4:c.1597A>G.
Still missing
  • No entry for c.1597A>G, p.Thr533Ala, or p.T533A was found in PALB2_PM3_BS2_1.3.pdf after searching all specified and broader variant notations.
  • Affected Fanconi Anemia proband observations and phase-confirmed pathogenic-variant co-occurrence data are unavailable.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3 ↗
PP1 VCEPNot assessed: no affected-relative segregation, meioses, LOD, or Bayes factor is documented for the variant. Details ▾Hide ▴
Reasoning

The VCEP PP1 rule requires, for the autosomal-dominant condition, segregation evidence quantified as LOD ≥1.26 or Bayes Factor (LR) ≥18:1 for strong, LOD ≥0.60 or Bayes Factor (LR) ≥4:1 for moderate, or LOD ≥0.3 or Bayes Factor (LR) ≥2:1 for supporting; the autosomal-recessive alternatives require segregation in at least 3, 2, or 1 affected relatives, respectively. The available case evidence contains no documented affected-relative segregation, parental testing, meioses, LOD, or Bayes factor for NM_024675.4:c.1597A>G, so PP1 cannot be evaluated.

VCEP rule
* AD Condition: LOD ≥1.26 or Bayes Factor (LR) ≥18:1 * AR Condition: Segregation in ≥3 affected relatives ... * AD Condition: LOD ≥.60 or Bayes Factor (LR) ≥4:1 * AR Condition: Segregation in 2 affected relatives ... * AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1 * AR Condition: Segregation in 1 affected relative
Evidence considered
  • PALB2 VCEP CSPEC PP1 rule: AD thresholds are LOD ≥1.26/0.60/0.3 or Bayes Factor ≥18:1/4:1/2:1 for strong/moderate/supporting; AR thresholds are segregation in ≥3/2/1 affected relatives for strong/moderate/supporting.
  • Case evidence review found no variant-specific affected-relative segregation, parental testing, meioses, LOD, or Bayes factor.
Still missing
  • Documented segregation in affected relatives with phase and phenotype information, or a VCEP-allowed LOD/Bayes factor calculation.
Sources
cspec ↗
BS2 VCEPNot assessed: gnomAD is excluded for BS2, and no qualifying clinical healthy-adult observation with the VCEP's required data is available. Details ▾Hide ▴
Reasoning

The PALB2 VCEP excludes population-based cohorts such as gnomAD from BS2. The available population records report no homozygotes, but they cannot be used for BS2. No clinical or research cohort observation of this missense variant in a healthy adult, with the VCEP's required phenotype, age, zygosity, phase, and co-occurring P/LP-variant information, is available in the reviewed case evidence. The governing PALB2_PM3_BS2_1.3.pdf table was searched for c.1597A>G, p.Thr533Ala, and p.T533A; no entry was found.

VCEP rule
Do not use for individuals in population based cohorts, such as gnomAD
Evidence considered
  • ClinGen PALB2 v1.3 CSPEC BS2 instructions state that Fanconi Anemia BS2 tables determine the points and final BS2 assignment, and that population-based cohorts such as gnomAD must not be used.
  • PALB2_PM3_BS2_1.3.pdf.txt was searched for c.1597A>G, p.Thr533Ala, and p.T533A; no matching entry was found.
  • gnomAD v2.1 and v4.1 report zero homozygotes, but these population-based observations are excluded from BS2 by the VCEP rule.
Still missing
  • No qualifying clinical or research cohort observation of PALB2 c.1597A>G / p.Thr533Ala / p.T533A with age, phenotype, zygosity, phase, and co-occurring P/LP-variant data.
  • No entry for c.1597A>G, p.Thr533Ala, or p.T533A was found in PALB2_PM3_BS2_1.3.pdf.txt, the governing PALB2 PM3/BS2 table file.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3 ↗
BS4 VCEPNot assessed: no informative non-segregation, LOD, or Bayes factor is documented for the variant. Details ▾Hide ▴
Reasoning

The VCEP BS4 rule assigns strong evidence at LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1, moderate evidence at LOD ≤ -.64 or Bayes Factor (LR) ≤.23, and supporting evidence at LOD ≤-.32 or Bayes Factor (LR) ≤.48. The available case evidence contains no documented non-segregation in informative affected relatives, LOD, or Bayes factor for NM_024675.4:c.1597A>G, so BS4 cannot be evaluated.

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 VCEP CSPEC BS4 rule: strong at LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1, moderate at LOD ≤ -.64 or Bayes Factor (LR) ≤.23, supporting at LOD ≤-.32 or Bayes Factor (LR) ≤.48.
  • Case evidence review found no variant-specific non-segregation data, informative relatives, LOD, or Bayes factor.
Still missing
  • Documented non-segregation in informative affected relatives with phenotype and testing details, or a VCEP-allowed LOD/Bayes factor calculation.
Sources
cspec ↗
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1597A>G is an exon 4 missense SNV, whereas the PALB2 PVS1 rule is limited to specified null variant classes. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PVS1 rule applies to null variants, specifically nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, and single- or multi-exon deletion variants in a gene where loss of function is a known disease mechanism. NM_024675.4:c.1597A>G, encoding p.(Thr533Ala)/p.(T533A), is an SNV missense variant in exon 4 and is not one of the specified null variant classes; therefore PVS1 is not applicable. The governing file PALB2_PVS1_v1.3.pdf was searched for c.1597A>G, p.Thr533Ala, and p.T533A, with no variant-specific entry found.

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
Evidence considered
  • vcep_materials.json, CSPEC criterion entry for PVS1: default strength Pathogenic Very Strong; rule is "Use PALB2 PVS1 Decision Tree".
  • pvs1_variant_assessment.json: NM_024675.4:c.1597A>G; p.(Thr533Ala)/p.(T533A); exon 4; consequence_class missense; canonical_splice_consensus false.
  • PALB2_PVS1_v1.3.pdf, PVS1 definition and decision-tree applicability: null variant classes are nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, and single- or multi-exon deletion; no row matched c.1597A>G, p.Thr533Ala, or p.T533A.
Still missing
  • No entry for c.1597A>G, p.Thr533Ala, or p.T533A was found in PALB2_PVS1_v1.3.pdf after searching all three notations.
Sources
cspec ↗pvs1_variant_assessmentvcep_palb2_pvs1_v1_3 ↗
PS1 N/ANot applicable: the PALB2 VCEP explicitly says not to use PS1 for missense changes, and this variant is p.Thr533Ala. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.1597A>G (p.Thr533Ala/p.T533A). The PALB2 VCEP PS1 guide explicitly excludes missense use because missense changes are not yet confirmed as a PALB2 disease mechanism; its splicing table therefore does not apply. Direct searches found no c.1597A>G, p.Thr533Ala, or p.T533A entry in PALB2_PS1_1.3.pdf.txt.

VCEP rule
* Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2
Evidence considered
  • PALB2_PS1_1.3.pdf, page 1, PS1 rule: missense changes are excluded and the table is limited to splicing variants.
  • Variant assessment: NM_024675.4:c.1597A>G is a missense variant encoding NP_078951.2:p.(Thr533Ala) / p.(T533A).
  • PALB2_PS1_1.3.pdf.txt was searched for c.1597A>G, p.Thr533Ala, and p.T533A; no matching entry was found.
Still missing
  • No c.1597A>G, p.Thr533Ala, or p.T533A entry was found in PALB2_PS1_1.3.pdf.txt; the VCEP's missense exclusion independently makes PS1 not applicable.
Sources
cspec ↗vcep_palb2_ps1_1_3 ↗pvs1_variant_assessment
PS2 VCEPNot applicable: the PALB2 VCEP explicitly designates PS2 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC entry explicitly marks PS2 as Not Applicable; therefore de novo evidence cannot be assigned under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 VCEP CSPEC criterion entry for PS2: applicability = Not Applicable.
Sources
cspec ↗
PS3 VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly marks PS3 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 CSPEC entry marks PS3 as not applicable. Therefore, functional assay evidence cannot be assigned as PS3 for this variant under the governing VCEP specification, regardless of assay validation, controls, or biological relevance.

VCEP rule
Not applicable
Evidence considered
  • PALB2 VCEP Version 1.3 CSPEC PS3 entry: applicability is "Not applicable"; the entry describes PS3 assay guidance but provides no applicable strength rule.
Sources
cspec ↗
PM1 VCEPNot applicable: the PALB2 VCEP CSPEC marks PM1 as Not Applicable, with no approved PALB2 domain table supplied. Details ▾Hide ▴
Reasoning

The PALB2 CSPEC entry marks PM1 as Not Applicable. The case's vcep_materials.json also has no domain_tables entry for PALB2, so no VCEP-approved critical-domain list is available to support a PM1 assignment.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 CSPEC criteria entry for PM1: applicability is Not Applicable.
  • vcep_materials.json domain_tables: no PALB2 entry was present; no domain boundary was used to override the VCEP applicability setting.
Sources
cspec ↗
PM4 VCEPNot applicable: the PALB2 VCEP CSPEC entry explicitly designates PM4 as Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC criterion entry explicitly marks PM4 as Not Applicable. The variant is an SNV missense substitution, with no protein-length change or other PM4 path available under this VCEP specification.

VCEP rule
Not Applicable
Evidence considered
  • vcep_materials.json, CSPEC criterion entry for PM4: applicability is "Not Applicable".
  • pvs1_variant_assessment.json: the variant is an exon 4 missense SNV, p.(Thr533Ala), not a protein-length-change event.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 is restricted to PVS1 Very Strong NMD-prone truncating variants, whereas this variant is missense p.Thr533Ala. Details ▾Hide ▴
Reasoning

The PALB2 VCEP PM5 rule is restricted to NMD-prone truncating DNA variants receiving PVS1 Very Strong with premature termination codons upstream of p.His1184. This variant is missense p.Thr533Ala, not a truncating variant, and no same-residue PM5 comparator is relevant under that governing rule.

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-variant PM5 applies only to NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.His1184.
  • Variant assessment: NM_024675.4:c.1597A>G is missense and encodes p.Thr533Ala.
  • pm5_candidates.json reports no eligible classic PM5 search candidates and identifies the PALB2 rule as truncation-cutoff/non-missense rather than classic same-residue missense PM5.
Sources
cspec ↗pm5_candidatespvs1_variant_assessment
PM6 VCEPNot applicable: the PALB2 VCEP explicitly designates PM6 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC entry explicitly marks PM6 as Not Applicable; therefore assumed de novo evidence cannot be assigned under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 VCEP CSPEC criterion entry for PM6: applicability = Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the PALB2 VCEP CSPEC explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 CSPEC entry explicitly marks PP2 as Not Applicable. No generic missense-mechanism or gene-level PP2 rule was substituted.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 CSPEC criteria entry for PP2: applicability is Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the PALB2 VCEP excludes PP4 for autosomal dominant breast cancer because its phenotype is not sufficiently specific to distinguish hereditary from sporadic disease. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PP4 as not applicable for this disease context: autosomal dominant breast cancer has multiple genetic etiologies and no readily distinguishing phenotype features; for autosomal recessive disease, phenotype considerations are handled through PM3.

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
  • The VCEP states that PP4 should not be used 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 ↗
PP5 VCEPNot applicable: the PALB2 VCEP explicitly prohibits PP5, regardless of external reports describing this variant as pathogenic. Details ▾Hide ▴
Reasoning

The PALB2 VCEP explicitly designates PP5 as 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
  • The VCEP PP5 entry is labeled 'Not Applicable for this VCEP' and instructs: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗
BS3 VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly marks BS3 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 CSPEC entry marks BS3 as not applicable. Therefore, functional assay evidence cannot be assigned as BS3 for this variant under the governing VCEP specification, regardless of assay validation, controls, or biological relevance.

VCEP rule
Not applicable
Evidence considered
  • PALB2 VCEP Version 1.3 CSPEC BS3 entry: applicability is "Not applicable"; the entry describes assay guidance but provides no applicable strength rule.
Sources
cspec ↗
BP2 VCEPNot applicable: the PALB2 Version 1.3 VCEP specification explicitly marks BP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC marks BP2 as Not Applicable. BP2 is therefore not evaluated for this variant under the governing PALB2 Version 1.3 specification.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 VCEP CSPEC criterion entry for BP2: applicability is listed as Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the PALB2 VCEP CSPEC entry explicitly designates BP3 as Not Applicable, and this is a missense SNV. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC criterion entry explicitly marks BP3 as Not Applicable. The variant is an SNV missense substitution rather than an in-frame deletion or insertion in a repetitive region, and the VCEP provides no BP3 path for this variant.

VCEP rule
Not Applicable
Evidence considered
  • vcep_materials.json, CSPEC criterion entry for BP3: applicability is "Not Applicable".
  • pvs1_variant_assessment.json: the variant is an exon 4 missense SNV, p.(Thr533Ala), not an in-frame deletion or insertion event.
Sources
cspec ↗
BP4 N/ANot applicable: the PALB2 VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI maximum delta score of 0.032. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP4 rule states that the missense path is not used and that the splicing path must not be applied for missense variants. Because NM_024675.4:c.1597A>G is a missense variant, BP4 is not applicable upstream of considering its 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
  • ClinGen PALB2 VCEP CSPEC BP4 rule: the missense path is not used, and the splicing path explicitly says not to apply BP4 for missense variants.
  • Variant consequence: NM_024675.4:c.1597A>G is annotated as missense, p.(Thr533Ala).
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants are expected and may not produce a distinguishable phenotype. Details ▾Hide ▴
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'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
  • The VCEP BP5 entry is labeled 'Not applicable' and states that cases with multiple pathogenic variants have been observed with no noticeable phenotype difference; PALB2's moderate penetrance also increases expected co-occurrence.
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 VCEP explicitly prohibits BP6, regardless of external reports describing this variant as benign. Details ▾Hide ▴
Reasoning

The PALB2 VCEP explicitly designates BP6 as 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
  • The VCEP BP6 entry is labeled 'Not Applicable for this VCEP' and instructs: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗
BP7 N/ANot applicable: BP7 covers synonymous or deep intronic variants, whereas NM_024675.4:c.1597A>G is an exonic missense variant. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP7 rule is limited to synonymous and deep intronic variants, with a separate RNA path for silent substitutions and intronic variants. NM_024675.4:c.1597A>G is a missense exonic variant, 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
  • ClinGen PALB2 VCEP CSPEC BP7 rule: the computational path is for synonymous and deep intronic variants, and the RNA path is for silent substitutions and intronic variants.
  • Variant consequence: NM_024675.4:c.1597A>G is annotated as missense, p.(Thr533Ala), not synonymous or intronic.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.1597A>G
Protein (HGVS p.)
NP_078951.2:p.(Thr533Ala)
GRCh38
chr16:23634949 T>C
GRCh37
chr16:23646270 T>C
Location and type
Exon 4 · missense
ClinVar
523534

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 7 / 1,614,064 alleles AF 4.34e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1 2 / 251,488 alleles AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 4.3e-06 · 7 / 1,614,064 alleles · 0 hom · FAF 1.8e-06
South Asian1 / 91,092 1.1e-05
European (non-Finnish)6 / 1,180,050 5.1e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,488 alleles · 0 hom
South Asian1 / 30,616 3.3e-05
European (non-Finnish)1 / 113,764 8.8e-06
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.33688e-06; MAF= 0.00043%, 7/1614064 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09779e-05; MAF= 0.00110%, 1/91092 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95267e-06; MAF= 0.00080%, 2/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -26 bp
0.032
SpliceAI acceptor gainat -1 bp
0.001
SpliceAI donor lossat -87 bp
0.004
SpliceAI donor gainat -245 bp
0.000
Pangolin splice lossmagnitude shown
-0.031
Pangolin splice gain
0.006

Other predictors

REVEL
0.028
BayesDel
-0.779

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta score is 0.032, below the VCEP PP3 threshold of ≥0.2 for predicted splice impact in missense variants. Details ▾Hide ▴
Reasoning

The PALB2 VCEP rule excludes the missense-protein path but permits PP3 for predicted splice impact in missense/in-frame variants. This variant is NM_024675.4:c.1597A>G, annotated as missense p.(Thr533Ala), and SpliceAI is the named predictor for this path. Its maximum delta score is 0.032, below the VCEP threshold of ≥0.2; therefore the VCEP PP3 splicing criterion is not met.

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
  • ClinGen PALB2 VCEP CSPEC PP3 rule: the missense path is excluded, while the splicing path applies to silent, missense/in-frame, and specified intronic variants using SpliceAI ≥0.2.
  • SpliceAI Lookup for NM_024675.4:c.1597A>G: DS_AG 0.001, DS_AL 0.032, DS_DG 0.000, DS_DL 0.004; maximum delta score 0.032. This is below the VCEP PP3 cutoff of ≥0.2.
Sources
cspec ↗spliceai ↗
BP4 N/ANot applicable: the PALB2 VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI maximum delta score of 0.032. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP4 rule states that the missense path is not used and that the splicing path must not be applied for missense variants. Because NM_024675.4:c.1597A>G is a missense variant, BP4 is not applicable upstream of considering its 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
  • ClinGen PALB2 VCEP CSPEC BP4 rule: the missense path is not used, and the splicing path explicitly says not to apply BP4 for missense variants.
  • Variant consequence: NM_024675.4:c.1597A>G is annotated as missense, p.(Thr533Ala).
Sources
cspec ↗
BP7 N/ANot applicable: BP7 covers synonymous or deep intronic variants, whereas NM_024675.4:c.1597A>G is an exonic missense variant. Details ▾Hide ▴
Reasoning

The PALB2 VCEP BP7 rule is limited to synonymous and deep intronic variants, with a separate RNA path for silent substitutions and intronic variants. NM_024675.4:c.1597A>G is a missense exonic variant, 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
  • ClinGen PALB2 VCEP CSPEC BP7 rule: the computational path is for synonymous and deep intronic variants, and the RNA path is for silent substitutions and intronic variants.
  • Variant consequence: NM_024675.4:c.1597A>G is annotated as missense, p.(Thr533Ala), not synonymous or intronic.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.028. BayesDel score = -0.778878.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
    2014
    No paper-specific finding is recorded.
    PMID 24366402 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389258 ↗
  • Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
    No paper-specific finding is recorded.
    PMID 31429903 ↗
  • Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.
    Breast Cancer Association Consortium et al. · 2021
    This large Breast Cancer Association Consortium case-control study analyzed 60,466 women with breast cancer and 53,461 controls. It reported aggregate associations for protein-truncating PALB2 variants and examined rare missense variants in aggregate, but did not report NM_024675.4:c.1597A>G or p.(T533A), so it supplies no variant-specific PS4 statistics.
    Does not name this variant
    PMID 33471991 ↗
    Quoted passage
    There was no evidence of a risk associated with missense variants in specific domains in BRCA2 (P = 0.27) or PALB2 (P = 0.48) (Tables S13, S17, and S18 and Figs. S1D and S1E).

    Results, Rare Missense Variants; Risk of Tumor Subtypes; Age Effects and Absolute Risk

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

gnomAD v4.1 7 / 1,614,064 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.032 Open source ↗
ClinVar 6 Uncertain significance · 1 Likely benign 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= 4.33688e-06; MAF= 0.00043%, 7/1614064 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09779e-05; MAF= 0.00110%, 1/91092 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95267e-06; MAF= 0.00080%, 2/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 523534)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.028. BayesDel score = -0.778878.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.

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.