0%
PALB2c.2856T>GUncertain significance
Print report
Variant interpretation report

PALB2 c.2856T>G, p.(Asp952Glu)

NM_024675.4:c.2856T>G NP_078951.2:p.(Asp952Glu) Missense · exon 9 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at Supporting: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 PM2 threshold of 0.000333%.

Benign criteria applied · 1
BP1Supporting
BP1 · supporting

Met at supporting strength: the PALB2 VCEP applies BP1 to all missense variants, and this variant is p.Asp952Glu.

Recorded classification: Uncertain significance

VUS: PALB2 VCEP Rule31 combines PM2 supporting for rarity with BP1 supporting for the missense consequence, yielding conflicting supporting evidence.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.026 recorded score

Recorded REVEL score: 0.026. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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: 2 met · 2 not met · 5 not assessed · 19 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

All requested consequence/LOF criteria are not applicable under the PALB2 VCEP Version 1.3 specification because the variant is missense p.(Asp952Glu), not a qualifying null, in-frame length-change, or repetitive-region deletion variant.

For PALB2 p.Asp952Glu, the governing VCEP makes BP1 supporting applicable to all missense variants while excluding PS1, PM1, PM5, and PP2 for this missense context.

PS2 and PM6 are not applicable under the PALB2 Version 1.3 VCEP.

PP1 and BS4 are applicable but cannot be assessed because no pedigree-level segregation, non-segregation, parental testing, meiosis counts, LOD score, or Bayes factor is available.

The PALB2 Version 1.3 VCEP governs this case and takes precedence over generic ACMG/AMP criteria.

PS4 is applicable in principle but cannot be assessed because no variant-specific case-control enrichment statistic is available.

PP4, PP5, BP5, and BP6 are explicitly not applicable under the governing PALB2 VCEP specification.

The governing PALB2 VCEP Version 1.3 was applied before predictor review.

NM_024675.4:c.2856T>G is a missense variant encoding p.Asp952Glu; PP3, BP4, and BP7 are all out of scope under their applicable PALB2 rules.

Met · 2

PM2 SupportingMet at Supporting: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 PM2 threshold of 0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 specifies PM2 at Supporting strength when the frequency is at most 1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with a single-observation exception. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 in all assessed populations and satisfies PM2 Supporting.

Rule
PALB2 VCEP v1.3: PM2 Supporting if frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; exception for n=1 in a single subpopulation
Evidence considered
  • The PALB2 ClinGen VCEP Version 1.3 PM2 Supporting rule is frequency <=1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency; the VCEP also permits a single-observation exception.
  • The queried variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed alternate alleles and therefore an observed frequency of 0 in every assessed population.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP1 SupportingMet at supporting strength: the PALB2 VCEP applies BP1 to all missense variants, and this variant is p.Asp952Glu. Details ▾Hide ▴
Reasoning

The variant is an exonic missense substitution, NM_024675.4:c.2856T>G, p.Asp952Glu. The PALB2 VCEP applies BP1 at supporting strength to all missense variants because PALB2 disease is primarily caused by truncating variants and pathogenic missense variants are thought to be exceedingly rare.

Rule
PALB2 VCEP BP1: apply at supporting strength to all missense variants.
Evidence considered
  • The variant is annotated as NM_024675.4:c.2856T>G, NP_078951.2:p.(Asp952Glu), with missense consequence.
  • The PALB2 Version 1.3 VCEP states that BP1 applies to all missense variants because true missense pathogenic variants are thought to be exceedingly rare, and specifies supporting strength.
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

BA1 Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BA1 threshold of >0.1%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 specifies BA1 when the gnomAD group maximum filtering allele frequency is greater than 0.1%. This missense variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 and does not meet the BA1 threshold.

Rule
PALB2 VCEP v1.3: Grpmax Filtering AF >0.1% in gnomAD
Evidence considered
  • The PALB2 ClinGen VCEP Version 1.3 rule is grpmax filtering AF >0.1% in gnomAD.
  • The queried variant is absent from gnomAD v2.1 and gnomAD v4.1; therefore no alternate allele was observed and the frequency is 0.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: gnomAD v2.1 and v4.1 report 0 observed alleles, below the PALB2 VCEP BS1 threshold of >0.01%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 specifies BS1 when the gnomAD group maximum filtering allele frequency is greater than 0.01%. This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0, which is below the BS1 threshold.

Rule
PALB2 VCEP v1.3: Grpmax Filtering AF >0.01% in gnomAD
Evidence considered
  • The PALB2 ClinGen VCEP Version 1.3 rule is grpmax filtering AF >0.01% in gnomAD.
  • The queried variant is absent from gnomAD v2.1 and gnomAD v4.1; therefore no alternate allele was observed and the frequency is 0.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 Not assessed: PALB2 VCEP PS4 requires p <= .05 and OR/HR/RR >=3 or lower 95% CI >=1.5, but no case-control estimate is available. Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP PS4 specification requires a case-control study with p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=3 or lower 95% CI >=1.5). The case materials contain no variant-specific case-control study, p-value, odds ratio, hazard ratio, relative risk, or confidence interval for NM_024675.4:c.2856T>G (NP_078951.2:p.(Asp952Glu)); therefore the criterion cannot be assessed.

Rule
Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=3 or lower 95% CI >=1.5).
Evidence considered
  • The PALB2 Version 1.3 VCEP states: "Case-control studies; p-value <=.05 **and** (Odds ratio, hazard ratio, or relative risk >=3 **or** lower 95% CI >=1.5)."
  • The available literature extracts do not report this exact PALB2 variant or provide variant-specific case-control enrichment data.
Still missing
  • A variant-specific case-control study with p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is unavailable.
Sources
cspec ↗PMID:15604628 ↗PMID:17508274 ↗PMID:24366376 ↗PMID:28492532 ↗PMID:34012068 ↗
PM3 Not assessed: no affected Fanconi anemia proband, pathogenic second allele, or phase information is documented, so the VCEP PM3 point total is unavailable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PM3 for the autosomal-recessive Fanconi anemia context and requires scoring affected probands according to the PM3 tables, with the variant confirmed in trans with a pathogenic or likely pathogenic PALB2 variant, or with phase unknown under the specified point system. The available case evidence documents no affected Fanconi anemia proband, second pathogenic PALB2 allele, phase determination, or qualifying clinical observations for NM_024675.4:c.2856T>G (p.Asp952Glu); therefore no PM3 points can be assigned. The VCEP thresholds are 1 point for supporting, 2 for moderate, 4 for strong, and 8 for very strong PM3, but the observed point total is not available.

Rule
PALB2 VCEP PM3: assign Fanconi anemia PM3 points per proband; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = at least 4 points, and PM3_VeryStrong = at least 8 points.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification applies PM3 to the autosomal-recessive Fanconi anemia context and directs point assignment per affected proband using its Fanconi anemia PM3 tables.
  • The VCEP PM3 thresholds are 1 point for supporting, 2 points for moderate, 4 points for strong, and 8 points for very strong.
  • The reviewed case evidence contains no qualifying affected Fanconi anemia proband, second pathogenic or likely pathogenic PALB2 allele, or phase result for this variant.
Still missing
  • Affected-proband observations compatible with PALB2-related Fanconi anemia are unavailable.
  • A pathogenic or likely pathogenic second PALB2 variant and its classification are unavailable.
  • Phase of NM_024675.4:c.2856T>G relative to a second PALB2 variant is unavailable.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3
PP1 Not assessed: no family segregation data or quantitative result is available to compare with the PP1 supporting threshold of LOD ≥0.3 or LR ≥2:1. Details ▾Hide ▴
Reasoning

PP1 is applicable under the PALB2 Version 1.3 VCEP, which mandates quantitative co-segregation analysis. No affected relatives, tested meioses, family pedigree, segregation counts, LOD score, or Bayes factor is provided for NM_024675.4:c.2856T>G (NP_078951.2:p.(Asp952Glu)); therefore no PP1 strength can be assigned. The VCEP thresholds are supporting at LOD ≥0.3 or LR ≥2:1, moderate at LOD ≥0.60 or LR ≥4:1, and strong at LOD ≥1.26 or LR ≥18:1.

Rule
PALB2 VCEP PP1: quantitative co-segregation required; supporting LOD ≥0.3 or LR ≥2:1, moderate LOD ≥0.60 or LR ≥4:1, strong LOD ≥1.26 or LR ≥18:1.
Evidence considered
  • The PALB2 Version 1.3 VCEP mandates quantitative co-segregation analysis for PALB2 alterations and defines PP1 supporting as LOD ≥0.3 or Bayes factor LR ≥2:1, moderate as LOD ≥0.60 or LR ≥4:1, and strong as LOD ≥1.26 or LR ≥18:1.
  • The available case evidence contains no proband pedigree, affected-relative segregation, tested meioses, LOD score, or Bayes factor for this variant.
Still missing
  • A family pedigree identifying affected and unaffected relatives is missing.
  • Genotype and phenotype results for informative relatives and the number of informative meioses are missing.
  • A quantitative co-segregation LOD score or Bayes factor is missing.
Sources
cspec ↗
BS2 Not assessed: gnomAD provides 0 observed alleles, but no qualifying healthy individual or homozygote observation is available for BS2. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 states that BS2 must not be applied to individuals in population-based cohorts such as gnomAD and requires assessment of qualifying healthy individuals, including the relevant zygosity and expected early penetrance. The available evidence contains only population-database absence and no individual-level healthy-adult observations, homozygote data, or documented penetrance assessment for this variant.

Rule
PALB2 VCEP v1.3: do not use BS2 for population-based cohorts such as gnomAD; assign BS2 from the Fanconi anemia BS2 point tables only when qualifying individual observations are available
Evidence considered
  • The PALB2 ClinGen VCEP Version 1.3 explicitly states not to use BS2 for individuals in population-based cohorts such as gnomAD.
  • The queried variant is absent from gnomAD v2.1 and gnomAD v4.1, so these databases provide no qualifying individual-level BS2 observation.
Still missing
  • Individual-level evidence from qualifying healthy adults, including zygosity and relevant disease penetrance, is unavailable.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS4 Not assessed: no non-segregation observations or quantitative result is available to compare with the BS4 supporting threshold of LOD ≤−0.32 or LR ≤0.48. Details ▾Hide ▴
Reasoning

BS4 is applicable under the PALB2 Version 1.3 VCEP, which requires quantitative co-segregation analysis and cautions that phenocopies and more than one pathogenic variant in a family can confound apparent lack of segregation. No affected relatives, tested meioses, family pedigree, non-segregation observations, LOD score, or Bayes factor is provided for NM_024675.4:c.2856T>G (NP_078951.2:p.(Asp952Glu)); therefore BS4 cannot be assigned at any strength. The VCEP thresholds are supporting at LOD ≤−0.32 or LR ≤0.48, moderate at LOD ≤−0.64 or LR ≤0.23, and strong at LOD ≤−1.28 or LR ≤0.053:1.

Rule
PALB2 VCEP BS4: quantitative co-segregation required; supporting LOD ≤−0.32 or LR ≤0.48, moderate LOD ≤−0.64 or LR ≤0.23, strong LOD ≤−1.28 or LR ≤0.053:1.
Evidence considered
  • The PALB2 Version 1.3 VCEP defines BS4 supporting as LOD ≤−0.32 or Bayes factor LR ≤0.48, moderate as LOD ≤−0.64 or LR ≤0.23, and strong as LOD ≤−1.28 or LR ≤0.053:1.
  • The specification cautions that phenocopies and multiple pathogenic variants can confound apparent lack of segregation, so non-segregation cannot be evaluated without family-level data.
  • The available case evidence contains no pedigree, informative meioses, discordant relatives, LOD score, or Bayes factor for this variant.
Still missing
  • A family pedigree identifying affected and unaffected relatives is missing.
  • Genotype and phenotype results for informative relatives and any discordant meioses are missing.
  • A quantitative co-segregation LOD score or Bayes factor is missing.
Sources
cspec ↗
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: PALB2 VCEP PVS1 is for null variants, whereas this variant is missense p.(Asp952Glu). Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 PVS1 specification applies PVS1 to null variants, including nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, and single- or multi-exon deletion variants. NM_024675.4:c.2856T>G is a missense variant, NP_078951.2:p.(Asp952Glu), and is not a null-variant consequence; therefore PVS1 is not applicable. No PVS1 strength tier is assigned.

Rule
PALB2 VCEP Version 1.3 PVS1 specification: null-variant applicability only
Evidence considered
  • PALB2 VCEP Version 1.3 defines PVS1 for null variants: nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, and single- or multi-exon deletions.
  • The case variant is NM_024675.4:c.2856T>G with protein consequence NP_078951.2:p.(Asp952Glu) and consequence class missense.
  • Because the variant is missense rather than a specified null variant, no PVS1 strength tier is assigned.
Sources
cspec ↗vcep_palb2_pvs1_v1_3
PS1 N/ANot applicable: PALB2 VCEP excludes PS1 for missense variants, and this variant is p.Asp952Glu rather than a demonstrated matching splice event. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies that PS1 must not be used for missense changes because missense is not yet confirmed as a PALB2 disease mechanism. The variant is the missense change p.Asp952Glu; the VCEP PS1 splicing table applies only when a variant has a matching predicted or observed splice event, which is not established here.

Rule
PALB2 VCEP PS1: missense do not use; splicing use the PALB2 PS1 splicing table only for matching predicted or observed splice events.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: Missense changes are not yet confirmed as a mechanism of disease for PALB2 and PS1 should not be used for missense.
  • The PALB2 PS1 table is restricted to splicing variants with the same predicted splicing event as a known likely pathogenic variant; this case is an exonic missense variant, p.Asp952Glu, with no demonstrated matching splice event.
Sources
cspec ↗vcep_palb2_ps1_1_3
PS2 VCEPNot applicable: the PALB2 VCEP explicitly excludes PS2 because informative de novo occurrences have not been observed for either PALB2 disease context. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.3 VCEP specification states that PS2 is not applicable for PALB2-related autosomal dominant disease because informative de novo occurrences have not been observed and breast cancer is common and genetically heterogeneous; it is also not applicable for the autosomal recessive condition because de novo occurrences are too rare to be informative and phase confirmation would generally require parental testing.

VCEP rule
PALB2 VCEP PS2: Not applicable; do not use for PALB2 autosomal dominant or autosomal recessive disease.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification designates PS2 not applicable for both autosomal dominant PALB2-related cancer predisposition and autosomal recessive Fanconi anemia.
  • The specification explains that de novo events are not informative for the autosomal dominant context and are too rare and difficult to phase reliably for the autosomal recessive context.
Sources
cspec ↗
PS3 VCEPNot applicable: PALB2 VCEP v1.3 designates PS3 as not applicable, so no functional assay result receives PS3 strength for this variant. Details ▾Hide ▴
Reasoning

The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification, version 1.3, designates PS3 as not applicable. Therefore, functional assay evidence cannot be assigned as PS3 for this PALB2 variant under the applicable framework, regardless of the absence of variant-specific assay results in the reviewed evidence.

VCEP rule
PALB2 VCEP v1.3: PS3 applicability = Not applicable.
Evidence considered
  • The PALB2 VCEP version 1.3 criterion table explicitly lists PS3 applicability as Not applicable.
  • The available case evidence contains no variant-specific validated protein-function or RNA assay result for NM_024675.4:c.2856T>G (NP_078951.2:p.(Asp952Glu)).
Sources
cspec ↗
PM1 VCEPNot applicable: PALB2 VCEP marks PM1 not applicable, and no approved domain-table entry or statistically significant D952 hotspot is available. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP specification marks PM1 as not applicable. The case's vcep_materials.json contains no PALB2 domain_tables entry, and no generic domain or hotspot inference can override the applicable VCEP rule. The hotspot source also reports no statistically significant hotspot for PALB2 D952.

VCEP rule
PALB2 VCEP PM1: not applicable.
Evidence considered
  • The PALB2 Version 1.3 VCEP lists PM1 as Not applicable.
  • vcep_materials.json has no PALB2 domain_tables entry to evaluate against residue 952.
  • The cancer-hotspot search reports that PALB2 D952 is not in a statistically significant hotspot.
Sources
cspec ↗
PM4 VCEPNot applicable: PALB2 VCEP explicitly marks PM4 not applicable, and c.2856T>G causes missense p.(Asp952Glu), not an in-frame length change. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 criteria specification explicitly marks PM4 as not applicable. Independently, this variant is a missense substitution, NM_024675.4:c.2856T>G, p.(Asp952Glu), not a protein-length change caused by an in-frame insertion or deletion. PM4 is therefore not applicable.

VCEP rule
PALB2 VCEP Version 1.3 PM4 applicability: Not Applicable
Evidence considered
  • PALB2 VCEP Version 1.3 explicitly lists PM4 as not applicable.
  • The variant is a missense substitution, NM_024675.4:c.2856T>G, producing NP_078951.2:p.(Asp952Glu), with no in-frame insertion or deletion or other protein-length change.
Sources
cspec ↗
PM5 N/ANot applicable: PALB2 VCEP PM5 is reserved for qualifying truncating or observed splice variants, whereas this variant is the missense change p.Asp952Glu. Details ▾Hide ▴
Reasoning

The PALB2 VCEP restricts PM5 to NMD-prone truncating variants upstream of p.His1184 that receive PVS1 Very Strong, including qualifying observed splice variants. It explicitly states not to use PM5 for missense changes. This variant is p.Asp952Glu.

Rule
PALB2 VCEP PM5: apply only to qualifying NMD-prone truncating or observed splice variants; do not use for missense.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: Do not use for missense changes; missense changes are not yet confirmed as a mechanism of disease for PALB2.
  • The governing PM5 rule applies to NMD-prone truncating variants upstream of p.His1184 with PVS1 Very Strong, or qualifying observed splice variants, not to same-residue missense comparisons.
  • The PM5 candidate artifact found no eligible classic same-residue missense search candidates and identifies the gene-specific rule as truncation-cutoff/non-missense.
Sources
cspec ↗pm5_candidates
PM6 VCEPNot applicable: the PALB2 VCEP explicitly excludes PM6 because assumed de novo occurrences are not informative in the PALB2 disease contexts. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.3 VCEP specification states that PM6 is not applicable for PALB2-related autosomal dominant disease because informative de novo occurrences have not been observed and the phenotype is genetically heterogeneous; it is also not applicable for the autosomal recessive condition because de novo occurrences are too rare to be informative.

VCEP rule
PALB2 VCEP PM6: Not applicable; do not use for PALB2 autosomal dominant or autosomal recessive disease.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification designates PM6 not applicable for both autosomal dominant PALB2-related cancer predisposition and autosomal recessive Fanconi anemia.
  • The specification states that assumed de novo status without confirmed maternity and paternity should not be used for these PALB2 disease contexts.
Sources
cspec ↗
PP2 VCEPNot applicable: PALB2 VCEP excludes PP2 because missense is not established as a disease mechanism, regardless of the REVEL score of 0.026. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP marks PP2 as not applicable and states that missense is not yet confirmed or refuted as a mechanism of disease for PALB2. Therefore the missense consequence and the REVEL score of 0.026 do not qualify for PP2.

VCEP rule
PALB2 VCEP PP2: not applicable; do not use because missense is not yet confirmed or refuted as a PALB2 disease mechanism.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.
  • The variant's REVEL score is 0.026, but PP2 is unavailable under the governing VCEP rule; this score is not used to infer PP2.
Sources
cspec ↗revel
PP3 N/ANot applicable: the PALB2 VCEP explicitly excludes missense variants from PP3, so no computational score is evaluated. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2856T>G (p.Asp952Glu). The governing PALB2 VCEP specification explicitly states that PP3 is not used for missense variants; its PP3 rule is restricted to predicted splice impact for silent, missense/in-frame, and intronic variants in the splicing context, while the missense baseline is explicitly 'Do not use.' Therefore PP3 is not applicable here, and no predictor score is evaluated for this criterion.

Rule
PALB2 VCEP v1.3 PP3: missense variants do not use PP3; splice-impact PP3 requires SpliceAI >=0.2 for the specified non-canonical splice contexts.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 specifies: 'Missense: Do not use' for PP3 and limits the applicable rule to predicted splice impact.
Sources
cspec ↗
PP4 VCEPNot applicable: the PALB2 VCEP excludes PP4 because breast cancer is genetically heterogeneous and lacks a sufficiently specific distinguishing phenotype. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specifies PP4 as not applicable. For autosomal dominant PALB2-related cancer predisposition, breast cancer has multiple genetic etiologies and no phenotype features readily distinguish hereditary from sporadic disease; for the autosomal recessive disorder, the VCEP directs phenotype considerations to PM3 instead.

VCEP rule
Do not use for AD disorder; for AR disorder, use PM3 for specific phenotype considerations.
Evidence considered
  • The PALB2 Version 1.3 VCEP marks PP4 as not applicable and states not to use it for autosomal dominant disease because breast cancer has multiple genetic etiologies and no readily distinguishing features.
Sources
cspec ↗
PP5 VCEPNot applicable: the PALB2 VCEP excludes PP5, and exact-variant ClinVar contains only a single-laboratory Uncertain significance assertion with no expert-panel classification. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact ClinVar record is a single-laboratory Uncertain significance assertion with no expert-panel submission, so it would not qualify under the requested exact-variant expert-panel rule in any event.

VCEP rule
Not Applicable for this VCEP; do not use PP5.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
  • ClinVar variation 963144 exactly matches NM_024675.4:c.2856T>G (p.Asp952Glu), but its only submission is Uncertain significance from one clinical laboratory with review status criteria provided, single submitter; expert-panel submissions: 0.
Sources
cspec ↗clinvar ↗PMID:15604628 ↗PMID:17508274 ↗PMID:24366376 ↗PMID:34012068 ↗
BS3 VCEPNot applicable: PALB2 VCEP v1.3 designates BS3 as not applicable, so no functional assay result receives BS3 strength for this variant. Details ▾Hide ▴
Reasoning

The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel PALB2 specification, version 1.3, designates BS3 as not applicable. Therefore, functional assay evidence cannot be assigned as BS3 for this PALB2 variant under the applicable framework, regardless of the absence of variant-specific assay results in the reviewed evidence.

VCEP rule
PALB2 VCEP v1.3: BS3 applicability = Not applicable.
Evidence considered
  • The PALB2 VCEP version 1.3 criterion table explicitly lists BS3 applicability as Not applicable.
  • The available case evidence contains no variant-specific validated protein-function or RNA assay result for NM_024675.4:c.2856T>G (NP_078951.2:p.(Asp952Glu)).
Sources
cspec ↗
BP2 VCEPNot applicable: the PALB2 VCEP explicitly excludes BP2 and provides no applicable strength rule for this criterion. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 specification explicitly marks BP2 as not applicable and provides no strength rule for it. Accordingly, observations of this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant are not evaluated under BP2 for PALB2.

VCEP rule
PALB2 VCEP BP2: Not applicable.
Evidence considered
  • The PALB2 Version 1.3 VCEP specification lists BP2 as not applicable and provides no applicable strength rule.
Sources
cspec ↗
BP3 VCEPNot applicable: PALB2 VCEP explicitly marks BP3 not applicable, and this variant is missense p.(Asp952Glu), not a repetitive-region in-frame deletion. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.3 criteria specification explicitly marks BP3 as not applicable. The variant is a missense substitution, NM_024675.4:c.2856T>G, p.(Asp952Glu), rather than an in-frame deletion in a repetitive region with no known function. BP3 is therefore not applicable.

VCEP rule
PALB2 VCEP Version 1.3 BP3 applicability: Not Applicable
Evidence considered
  • PALB2 VCEP Version 1.3 explicitly lists BP3 as not applicable.
  • The variant is a missense substitution, NM_024675.4:c.2856T>G, producing NP_078951.2:p.(Asp952Glu), not an in-frame deletion in a repetitive region.
Sources
cspec ↗
BP4 N/ANot applicable: the PALB2 VCEP excludes missense variants from BP4, so REVEL and SpliceAI scores are not evaluated. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2856T>G (p.Asp952Glu). The governing PALB2 VCEP specification explicitly states that BP4 is not used for missense variants and restricts BP4 to no predicted splice impact for splicing variants using SpliceAI <=0.1. Therefore BP4 is not applicable, and the available REVEL and SpliceAI scores are not evaluated for this criterion.

Rule
PALB2 VCEP v1.3 BP4: missense variants do not use BP4; splice-impact BP4 requires SpliceAI <=0.1.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 specifies: 'Missense: Do not use' for BP4; BP4 is reserved for no predicted splicing impact via SpliceAI <=0.1.
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP excludes BP5 because co-occurring pathogenic variants may not alter phenotype and PALB2 has moderate penetrance. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP5 as not applicable and instructs reviewers 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; criterion is not applicable for PALB2.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype ... PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently."
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 VCEP excludes BP6, and exact-variant ClinVar has no expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact ClinVar record has no expert-panel benign or likely benign classification; it is a single-laboratory Uncertain significance assertion.

VCEP rule
Not Applicable for this VCEP; do not use BP6.
Evidence considered
  • The PALB2 Version 1.3 VCEP states: "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
  • ClinVar variation 963144 exactly matches NM_024675.4:c.2856T>G (p.Asp952Glu), but its only submission is Uncertain significance from one clinical laboratory with review status criteria provided, single submitter; expert-panel submissions: 0.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: the variant changes Asp952 to Glu rather than being synonymous, whereas BP7 is limited to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

The variant is missense, NM_024675.4:c.2856T>G (p.Asp952Glu), not synonymous. BP7 is restricted to synonymous and qualifying deep intronic variants under the governing PALB2 VCEP specification, so BP7 is not applicable and no splice prediction is evaluated for it.

Rule
PALB2 VCEP v1.3 BP7: use for synonymous and qualifying deep intronic variants; not applicable to missense variants.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 limits BP7 to synonymous and qualifying deep intronic variants.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.2856T>G
Protein (HGVS p.)
NP_078951.2:p.(Asp952Glu)
GRCh38
chr16:23623109 A>C
GRCh37
chr16:23634430 A>C
Location and type
Exon 9 · missense
ClinVar
963144

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -9 bp
0.014
SpliceAI acceptor gainat -1 bp
0.136
SpliceAI donor lossat -140 bp
0.003
SpliceAI donor gainat -1 bp
0.000

Other predictors

REVEL
0.026
BayesDel
-0.670

How the predictions were used

PP3 N/ANot applicable: the PALB2 VCEP explicitly excludes missense variants from PP3, so no computational score is evaluated. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2856T>G (p.Asp952Glu). The governing PALB2 VCEP specification explicitly states that PP3 is not used for missense variants; its PP3 rule is restricted to predicted splice impact for silent, missense/in-frame, and intronic variants in the splicing context, while the missense baseline is explicitly 'Do not use.' Therefore PP3 is not applicable here, and no predictor score is evaluated for this criterion.

Rule
PALB2 VCEP v1.3 PP3: missense variants do not use PP3; splice-impact PP3 requires SpliceAI >=0.2 for the specified non-canonical splice contexts.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 specifies: 'Missense: Do not use' for PP3 and limits the applicable rule to predicted splice impact.
Sources
cspec ↗
BP4 N/ANot applicable: the PALB2 VCEP excludes missense variants from BP4, so REVEL and SpliceAI scores are not evaluated. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2856T>G (p.Asp952Glu). The governing PALB2 VCEP specification explicitly states that BP4 is not used for missense variants and restricts BP4 to no predicted splice impact for splicing variants using SpliceAI <=0.1. Therefore BP4 is not applicable, and the available REVEL and SpliceAI scores are not evaluated for this criterion.

Rule
PALB2 VCEP v1.3 BP4: missense variants do not use BP4; splice-impact BP4 requires SpliceAI <=0.1.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 specifies: 'Missense: Do not use' for BP4; BP4 is reserved for no predicted splicing impact via SpliceAI <=0.1.
Sources
cspec ↗
BP7 N/ANot applicable: the variant changes Asp952 to Glu rather than being synonymous, whereas BP7 is limited to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

The variant is missense, NM_024675.4:c.2856T>G (p.Asp952Glu), not synonymous. BP7 is restricted to synonymous and qualifying deep intronic variants under the governing PALB2 VCEP specification, so BP7 is not applicable and no splice prediction is evaluated for it.

Rule
PALB2 VCEP v1.3 BP7: use for synonymous and qualifying deep intronic variants; not applicable to missense variants.
Evidence considered
  • ClinGen PALB2 VCEP Version 1.3 limits BP7 to synonymous and qualifying deep intronic variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.026. BayesDel score = -0.670448.

6 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

  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    This paper presents general recommendations for cancer genetic risk assessment and counseling and does not report data specific to PALB2, c.2856T>G, or NP_078951.2:p.(D952E).
    Does not name this variant
    PMID 15604628 ↗
    Quoted passage
    The guidelines are intended to provide background information on the process of genetic counseling and risk assessment for hereditary cancer rather than to provide information about specific hereditary cancer syndromes.

    Purpose

  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    This paper does not mention PALB2 or the specific variant c.2856T>G / NP_078951.2:p.(D952E) and provides no variant-specific case-control, phenotype, or classification evidence.
    Does not name this variant
    PMID 17508274 ↗
  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    Moyer VA et al. · 2014
    The paper does not mention PALB2 or the specific variant c.2856T>G / NP_078951.2:p.(D952E); it discusses BRCA1 and BRCA2 screening and provides no variant-specific enrichment or classification evidence.
    Does not name this variant
    PMID 24366376 ↗
    Quoted passage
    The USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2).

    Summary of Recommendations and Evidence

  • PMID 24432435
    Nelson HD et al. · 2013
    No paper-specific finding is recorded.
    PMID 24432435 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite
    The provided paper text presents the general Sherloc variant-classification framework and does not explicitly mention PALB2, c.2856T>G, or NP_078951.2:p.(D952E); it supplies no variant-specific case-control or expert-panel classification evidence.
    Does not name this variant
    PMID 28492532 ↗
    Quoted passage
    Consistent with the ACMG–AMP guidelines, Sherloc is a system for the evaluation of constitutional variants within a Mendelian disease framework.

    Introduction

  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    Miller DT et al. · 2021
    The paper does not mention PALB2 c.2856T>G or p.(D952E); it gives gene-level PALB2 cancer-risk estimates for pathogenic variants from 524 families, not variant-specific case-control evidence or an exact-variant classification.
    Does not name this variant
    PMID 34012068 ↗
    Quoted passage
    A recent, international study of individuals heterozygous for a PALB2 pathogenic variant from 524 families estimated that the absolute risk of developing breast cancer by age 80 years varies from 52% (95% CI: 42–62%) for a female with an unaffected mother at age 50 years and unaffected maternal grandmother at age 70 years to 76% (95% CI: 69–83%) for a female with two affected first-degree relatives.

    Considerations for Specific Phenotype Categories, Genes related to cancer phenotypes, Recommended for addition to the SF v3.0 list

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.136 Open source ↗
ClinVar 1 Uncertain significance 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 963144)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.026. BayesDel score = -0.670448.

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.