0%
PALB2c.829G>ALikely benign
Print report
Variant interpretation report

PALB2 c.829G>A, p.(Asp277Asn)

NM_024675.4:c.829G>A NP_078951.2:p.(Asp277Asn) Missense · exon 4 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

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

In plain language

Gene-level background from the recorded interpretation.

About PALB2

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

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen PALB2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BP1Supporting
BP1 · supporting

Met (Supporting): BP1 applies to all missense variants under the PALB2 rules, and c.829G>A is missense (p.Asp277Asn).

BP4Supporting
BP4 · supporting

Met (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact.

Recorded classification: Likely benign

Rule19 (Benign Supporting >=2) is satisfied by BP1 and BP4 at supporting strength, giving an overall classification of Likely Benign.

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
13 / 1,613,948 alleles

gnomAD v4.1: 13 / 1,613,948 alleles. Recorded AF 8.05478e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.12158e-05; MAF= 0.00212%, 6/282808 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01282e-05; MAF= 0.00801%, 2/24960 alleles, homozygotes = 0); grpmax FAF= 3.98e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

Recorded REVEL score: 0.006. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
7 reported laboratory submissions

4 Uncertain significance · 2 Likely benign · 1 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
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55167240, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 5 not met · 5 not assessed · 16 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

For PALB2, the applicable VCEP framework explicitly marks both PS3 and BS3 as Not Applicable; no generic ACMG functional criterion is substituted.

Met · 2

BP1 SupportingMet (Supporting): BP1 applies to all missense variants under the PALB2 rules, and c.829G>A is missense (p.Asp277Asn). Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP framework instructs that BP1 applies to all missense variants. NM_024675.4:c.829G>A is a missense variant resulting in p.Asp277Asn; BP1 is therefore met at supporting strength.

Rule
Apply to all missense variants.
Evidence considered
  • The PALB2 Version 1.2 VCEP BP1 rule states: Apply to all missense variants.
  • Case normalization identifies NM_024675.4:c.829G>A as NP_078951.2:p.(Asp277Asn), confirming a missense consequence.
Sources
cspec ↗
BP4 SupportingMet (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact. Details ▾Hide ▴
Reasoning

The PALB2 VCEP directs splice analysis for all variant types and assigns BP4_Supporting when SpliceAI is <=0.1. This missense variant has a maximum SpliceAI delta of 0.002, meeting that calibrated splice-prediction threshold. BP4 is applied once through the splicing path; REVEL and BayesDel are not additionally counted.

Rule
PALB2 VCEP BP4_Supporting: apply for no predicted splice impact when SpliceAI <=0.1; use the splice path only, not missense protein predictors.
Evidence considered
  • PALB2 VCEP BP4: splice analysis must be considered for all variant types and BP4 is assigned for no predicted splice impact at SpliceAI <=0.1; the VCEP does not permit missense protein-predictor BP4 evidence for PALB2.
  • SpliceAI for NM_024675.4:c.829G>A reports a maximum delta score of 0.002, below the VCEP BP4 cutoff of 0.1.
  • REVEL 0.006 and BayesDel -0.862298 were not counted, preventing duplicate computational evidence and respecting the VCEP exclusion of PALB2 missense protein predictors; BayesDel lacks a verified calibrated threshold publication/table in this case.
Still missing
  • No variant-specific RNA splicing assay is provided; if a future assay demonstrates a substantial splice defect, re-adjudicate PP3/BP4 under the PALB2 VCEP RNA guidance.
Sources
cspec ↗spliceai ↗revelbayesdel

Not met · 5 · evaluated, threshold not reached

PVS1 Not met: c.829G>A is a missense change (p.Asp277Asn), not a loss-of-function variant, with no predicted splice defect (SpliceAI max delta 0.002). Details ▾Hide ▴
Reasoning

NM_024675.4:c.829G>A is the missense variant p.(Asp277Asn), not a predicted loss-of-function variant. The PALB2-specific PVS1 specification directs use of its PVS1 decision tree; its premise is not met. SpliceAI has a maximum delta score of 0.002, providing no evidence that this coding substitution creates a splice defect that could result in a null transcript or NMD.

Rule
PALB2 VCEP PVS1: use the PALB2 PVS1 Decision Tree; not met because this is a missense substitution without predicted splice disruption.
Evidence considered
  • The PALB2 VCEP specification (version 1.2) specifies that PVS1 strength is determined with the PALB2 PVS1 Decision Tree.
  • Variant normalization identifies NM_024675.4:c.829G>A as NP_078951.2:p.(Asp277Asn), a single amino-acid substitution.
  • SpliceAI reports DS_AG 0.000, DS_AL 0.000, DS_DG 0.002, and DS_DL 0.001 (maximum delta 0.002), indicating no predicted splice impact.
Sources
cspec ↗spliceai ↗
PM2 Not met: gnomAD v4.1 total allele frequency 0.000805% exceeds the PM2 Supporting cutoff of <=0.000333% (1 in 300,000). Details ▾Hide ▴
Reasoning

PM2 is not met under the PALB2 VCEP v1.2 rule. The VCEP permits PM2_Supporting only when frequency is ≤1/300,000 (0.000333%) in gnomAD v4.1. This variant is present in gnomAD v4.1 at total AF 8.05478e-06 (0.000805%), with grpmax FAF 2.55e-05 (0.00255%) and highest subpopulation AF 6.6745e-05 (0.00667%), all above the PM2 cutoff. The under-represented-subpopulation exception applies to n=1 with frequency >0.0003%; the highest subpopulation observation has 5 alleles, so that exception does not apply.

Rule
Frequency ≤ 1/300,000 (0.000333%) in gnomAD v4 dataset; use as PM2_Supporting only
Evidence considered
  • The PALB2 ClinGen VCEP v1.2 specifies PM2_Supporting at frequency ≤1/300,000 (0.000333%) in gnomAD v4.1 and notes an exception for an under-represented subpopulation with n=1 and frequency >0.0003%.
  • gnomAD v4.1 reports the variant in 13/1,613,948 alleles with total AF 8.054782434130468e-06 (0.000805%), zero homozygotes, grpmax FAF 2.55e-05, and 5/74,912 alleles in the highest-frequency African/African American population (AF 6.674498077744554e-05).
  • The total frequency exceeds the VCEP PM2 cutoff, and the n=1 under-represented-subpopulation exception is not applicable because the highest-frequency subpopulation has allele count 5.
Sources
cspec ↗gnomad_v4 ↗
PP3 Not met: SpliceAI max delta 0.002 falls below the >=0.2 threshold required for PP3 splice evidence. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specification restricts PP3 for missense variants to predicted splice impact and requires SpliceAI >=0.2. The observed maximum SpliceAI delta is 0.002, so the PP3 splice threshold is not met. Protein-level missense predictors are not used because this VCEP explicitly states that published predictors have not achieved functional outcome for PALB2 missense variants.

Rule
PALB2 VCEP PP3 (Supporting): for non-canonical splice variants, apply only when SpliceAI >=0.2; missense protein-predictor evidence is not used.
Evidence considered
  • PALB2 VCEP PP3: assess splice impact for all variant types; apply PP3 only for SpliceAI >=0.2, and do not use missense protein predictors because published predictors have not achieved functional outcome for PALB2 missense variants.
  • SpliceAI for NM_024675.4:c.829G>A reports DS_AG 0.000, DS_AL 0.000, DS_DG 0.002, DS_DL 0.001; maximum delta 0.002.
  • REVEL 0.006 and BayesDel -0.862298 were not used for PP3: the governing PALB2 VCEP excludes missense protein-predictor use, and no verified BayesDel calibration publication/table is available in this case.
Still missing
  • No variant-specific RNA splicing assay is provided; a future assay demonstrating a substantial splice defect would require re-adjudication under the PALB2 VCEP RNA guidance.
Sources
cspec ↗spliceai ↗revelbayesdel
BA1 Not met: gnomAD v4.1 grpmax FAF 0.00255% is well below the >0.1% BA1 population-frequency threshold. Details ▾Hide ▴
Reasoning

BA1 is not met. The PALB2 VCEP v1.2 threshold is grpmax filtering AF >0.1% in gnomAD v4.1. The observed gnomAD v4.1 grpmax FAF is 2.55e-05 (0.00255%), substantially below 0.1%; the highest subpopulation AF is 6.6745e-05 (0.00667%), also below the threshold.

Rule
Grpmax Filtering AF >0.1% in gnomAD v4 dataset
Evidence considered
  • The PALB2 ClinGen VCEP v1.2 specifies BA1 at grpmax filtering AF >0.1% in gnomAD v4.1.
  • gnomAD v4.1 reports total AF 8.05478e-06 (13/1,613,948 alleles), grpmax FAF 2.55e-05, and highest observed subpopulation AF 6.674498077744554e-05 in the African/African American population.
  • These frequencies are below the BA1 threshold; no threshold-supporting benign stand-alone population evidence is present.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: gnomAD v4.1 grpmax FAF 0.00255% is below the >0.01% BS1 population-frequency threshold. Details ▾Hide ▴
Reasoning

BS1 is not met. The PALB2 VCEP v1.2 threshold is grpmax filtering AF >0.01% in gnomAD v4.1. The observed gnomAD v4.1 grpmax FAF is 2.55e-05 (0.00255%), and the highest subpopulation AF is 6.6745e-05 (0.00667%); both are below 0.01%.

Rule
Grpmax Filtering AF >0.01% in gnomAD v4 dataset
Evidence considered
  • The PALB2 ClinGen VCEP v1.2 specifies BS1 at grpmax filtering AF >0.01% in gnomAD v4.1.
  • gnomAD v4.1 reports grpmax FAF 2.55e-05 (0.00255%) and highest observed subpopulation AF 6.674498077744554e-05 (0.00667%).
  • Neither the overall maximum group frequency nor the highest ancestry frequency exceeds the VCEP BS1 threshold.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 Not assessed: no case-control study reporting this exact variant was available to test the required p<=0.05 with risk ratio >=3. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specification permits PS4 at Strong only with a case-control result having p<=0.05 and an odds ratio, hazard ratio, or relative risk >=3 (or lower 95% CI >=1.5). No exact-variant case-control enrichment result for c.829G>A (p.Asp277Asn) was identified. The available PALB2 case-control study reports only aggregate missense/domain associations and explicitly does not report this variant.

Rule
PALB2 VCEP v1.2 PS4 Strong: case-control p-value <=0.05 AND odds ratio, hazard ratio, or relative risk >=3 OR lower 95% CI >=1.5.
Evidence considered
  • PALB2 VCEP v1.2 PS4 requires a case-control p-value <=0.05 and an odds ratio, hazard ratio, or relative risk >=3, or a lower 95% confidence-limit >=1.5.
  • PMID:28779002 selectively reviewed extraction states that c.829G>A/p.(D277N) is not explicitly reported; its OR=1.76 result is an aggregate signal across 29 rare N-terminal PALB2 missense variants, not an estimate for this variant.
Still missing
  • Exact-variant case and control counts or a qualified case-control effect estimate with confidence interval and p-value are unavailable.
Sources
cspec ↗PMID:28779002 ↗
PM3 Not assessed: no biallelic observations, second PALB2 variant, or phase data were available for the recessive Fanconi anemia condition. Details ▾Hide ▴
Reasoning

The PALB2 VCEP framework makes PM3 applicable for the autosomal-recessive Fanconi anemia complementation group N condition and requires proband-level scoring based on biallelic observations, including phase with a pathogenic or likely pathogenic variant. The case bundle contains no affected-proband observation, second PALB2 variant, parental/offspring testing, or documented cis/trans phase for NM_024675.4:c.829G>A (p.Asp277Asn); therefore PM3 cannot be assigned.

Rule
PALB2 VCEP PM3: assign per-proband Fanconi anemia PM3 points; PM3 Supporting = 1 point, PM3 Moderate = 2 points, PM3 Strong = at least 4 points, and PM3 Very Strong = at least 8 points.
Evidence considered
  • The PALB2 VCEP Version 1.2 specification states that PM3 is applicable for the recessive Fanconi anemia condition and directs curators to the Fanconi anemia PM3 tables for per-proband points and final strength assignment.
  • The consolidated case-evidence bundle provides no affected-proband, biallelic, co-occurrence, parental, offspring, or cis/trans phase evidence for this variant.
Still missing
  • Affected-proband phenotype consistent with Fanconi anemia is not documented.
  • No pathogenic or likely pathogenic PALB2 variant in the same proband is documented.
  • No parental, offspring, or other phasing data establish the variants as in trans.
  • No per-proband PM3 point assignment is possible from the available evidence.
Sources
cspec ↗
PP1 Not assessed: no segregation evidence (affected relatives, LOD score, or Bayes factor) was available. Details ▾Hide ▴
Reasoning

The PALB2 VCEP permits PP1 using segregation evidence: for autosomal dominant disease, Supporting requires LOD >=0.3 or Bayes factor >=2:1, Moderate requires LOD >=0.60 or Bayes factor >=4:1, and Strong requires LOD >=1.26 or Bayes factor >=18:1; for autosomal recessive disease, the specified thresholds are one, two, or at least three affected relatives for Supporting, Moderate, or Strong, respectively. The case-evidence bundle provides no documented affected relatives, variant-positive relatives, meioses, pedigree segregation, phenotype concordance, LOD, or Bayes factor from which to apply PP1.

Rule
AD: Supporting LOD >=0.3 or Bayes factor >=2:1; Moderate LOD >=0.60 or Bayes factor >=4:1; Strong LOD >=1.26 or Bayes factor >=18:1. AR: Supporting segregation in 1 affected relative; Moderate in 2 affected relatives; Strong in >=3 affected relatives.
Evidence considered
  • The governing PALB2 VCEP PP1 rules specify AD thresholds of LOD >=0.3, >=0.60, and >=1.26 or Bayes factor >=2:1, >=4:1, and >=18:1 for Supporting, Moderate, and Strong, respectively, and AR thresholds based on segregation in one, two, or at least three affected relatives.
  • Review of the consolidated case-evidence bundle found no proband-relative segregation data, informative meioses, pedigree genotypes, phenotype concordance data, LOD, or Bayes factor for this variant.
Still missing
  • Documented pedigree with affected and unaffected relatives
  • Genotypes of informative relatives and confirmed phase
  • Number of informative meioses
  • Segregation LOD or Bayes factor, or sufficient data to calculate it
  • Phenotype consistency in relatives
Sources
cspec ↗
BS2 Not assessed: no healthy adults with this genotype and adequate age context were documented; population databases cannot be used for BS2. Details ▾Hide ▴
Reasoning

BS2 cannot be established from the available evidence. gnomAD v4.1 reports zero homozygotes, but the PALB2 VCEP specifically prohibits using population-based cohorts such as gnomAD for BS2. No qualifying healthy adult individual with an appropriate genotype and adequate age/penetrance context is documented in the case bundle.

Rule
BS2: do not use individuals in population-based cohorts such as gnomAD; otherwise assign strength from the PALB2 Fanconi Anemia BS2 point tables
Evidence considered
  • The PALB2 ClinGen VCEP v1.2 states that BS2 should not be used for individuals in population-based cohorts such as gnomAD and assigns BS2 strength by the Fanconi anemia BS2 point tables.
  • gnomAD v4.1 reports 0 homozygotes among 1,613,948 alleles, but this population observation is excluded from BS2 by the VCEP rule.
  • The bundle contains no qualifying healthy-adult case observation, age-of-onset information, or penetrance-adjusted genotype assessment for BS2.
Still missing
  • No qualifying non-population observation of the variant in a healthy adult with genotype, age, phenotype, and penetrance context was provided.
  • A case-level assessment of whether the individual is sufficiently past the expected age of disease onset is unavailable.
Sources
cspec ↗gnomad_v4 ↗
BS4 Not assessed: no family data showing absence of segregation (LOD score or Bayes factor) were available. Details ▾Hide ▴
Reasoning

The PALB2 VCEP permits BS4 for lack of segregation when the evidence reaches the specified threshold: Supporting at LOD <=-0.32 or Bayes factor <=0.48, Moderate at LOD <=-0.64 or Bayes factor <=0.23, and Strong at LOD <=-1.28 or Bayes factor <=0.053:1. The case-evidence bundle contains no documented non-segregation, unaffected variant-negative or affected variant-negative relatives, informative meioses, LOD, or Bayes factor; therefore BS4 cannot be assigned.

Rule
Strong: LOD <=-1.28 or Bayes factor (LR) <=0.053:1; Moderate: LOD <=-0.64 or Bayes factor (LR) <=0.23; Supporting: LOD <=-0.32 or Bayes factor (LR) <=0.48.
Evidence considered
  • The governing PALB2 VCEP BS4 rules specify Supporting at LOD <=-0.32 or Bayes factor <=0.48, Moderate at LOD <=-0.64 or Bayes factor <=0.23, and Strong at LOD <=-1.28 or Bayes factor <=0.053:1.
  • Review of the consolidated case-evidence bundle found no documented non-segregation observations, informative relatives, meioses, LOD, or Bayes factor for this variant.
Still missing
  • Documented non-segregating relatives with phenotype and genotype
  • Number of informative meioses and family structure
  • LOD or Bayes factor demonstrating lack of segregation
  • Assessment of phenocopies, reduced penetrance, and variant-testing quality
Sources
cspec ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: PS1 is restricted to the PALB2 splicing table, and this is a missense substitution without significant predicted splice impact. Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP framework restricts PS1 to the PALB2 PS1 splicing table. This variant is a missense substitution, NM_024675.4:c.829G>A (p.Asp277Asn), and the case evidence reports no significant predicted splice impact (SpliceAI maximum delta score 0.002); therefore PS1 is not applicable.

Rule
Use PALB2 PS1 Splicing table
Evidence considered
  • The PALB2 Version 1.2 VCEP specification defines PS1 only through the PALB2 PS1 splicing table.
  • The case variant is annotated as NM_024675.4:c.829G>A (NP_078951.2:p.(Asp277Asn)), a missense substitution.
  • SpliceAI reports a maximum delta score of 0.002, with no significant predicted splice impact.
Sources
cspec ↗spliceai ↗
PS2 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PS2 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, explicitly designates PS2 as not applicable.

VCEP rule
Not Applicable
Evidence considered
  • The governing PALB2 VCEP specification explicitly lists PS2 as Not Applicable; generic ACMG PS2 was not used.
Sources
cspec ↗
PS3 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PS3 as not applicable. Details ▾Hide ▴
Reasoning

The applicable PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, explicitly designates PS3 as Not Applicable. Therefore, PS3 cannot be assigned for this variant under the governing framework, regardless of the absence or presence of generic functional-assay evidence.

VCEP rule
ClinGen PALB2 VCEP Version 1.2: PS3 applicability = Not Applicable.
Evidence considered
  • The PALB2 VCEP specification is the governing framework and lists PS3 as Not Applicable.
  • The ACMG/AMP standards paper was consulted for general principles that functional evidence should come from biologically relevant, validated, reproducible, and robust assays; it reports no PALB2-specific assay or result for NM_024675.4:c.829G>A (NP_078951.2:p.(Asp277Asn)).
Still missing
  • No variant-specific validated functional assay result is available in the case evidence bundle; however, this gap does not change the VCEP-defined Not Applicable disposition.
Sources
cspec ↗PMID:25741868 ↗
PM1 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PM1 as not applicable. Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP framework explicitly designates PM1 as not applicable. The case vcep_materials.json domain_tables object is empty, and no generic PM1 domain inference is used to override the gene-specific specification.

Evidence considered
  • The PALB2 Version 1.2 VCEP framework lists PM1 as Not Applicable.
  • The case vcep_materials.json domain_tables key is present but empty; therefore there is no authoritative PALB2 domain-table entry to apply.
Sources
cspec ↗PMID:28779002 ↗
PM4 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PM4 as not applicable. Details ▾Hide ▴
Reasoning

PM4 is explicitly designated Not Applicable in the PALB2 VCEP specification. Independently, p.(Asp277Asn) is a one-residue substitution and does not change protein length or create an in-frame insertion/deletion or stop-loss consequence.

VCEP rule
PALB2 VCEP PM4: Not Applicable.
Evidence considered
  • The PALB2 VCEP specification (version 1.2) lists PM4 as Not Applicable.
  • Variant normalization identifies the consequence as NP_078951.2:p.(Asp277Asn), with no protein-length change.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 applies only to truncating or frameshifting variants upstream of p.Tyr1183, not to missense changes. Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP PM5 rule applies to frameshifting or truncating variants upstream of p.Tyr1183, or qualifying splice variants with observed splicing impact and NMD susceptibility. NM_024675.4:c.829G>A produces the missense change p.Asp277Asn and has no significant predicted splice impact, so PM5 is not applicable.

Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183; apply to qualifying splice variants with observed high-quality splicing impact and NMD susceptibility.
Evidence considered
  • The PALB2 Version 1.2 VCEP PM5 rule is limited to qualifying frameshifting/truncating or qualifying splice variants.
  • The case variant is NM_024675.4:c.829G>A (p.Asp277Asn), a missense substitution.
  • SpliceAI reports a maximum delta score of 0.002 and no significant predicted splice impact.
Sources
cspec ↗spliceai ↗
PM6 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PM6 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, explicitly designates PM6 as not applicable.

VCEP rule
Not Applicable
Evidence considered
  • The governing PALB2 VCEP specification explicitly lists PM6 as Not Applicable; generic ACMG PM6 was not used.
Sources
cspec ↗
PP2 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PP2 as not applicable. Details ▾Hide ▴
Reasoning

The applicable PALB2 VCEP framework explicitly designates PP2 as not applicable. No generic gene-level missense-mechanism PP2 assertion is made in preference to the gene-specific specification.

Evidence considered
  • The PALB2 Version 1.2 VCEP framework lists PP2 as Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PP4 as not applicable. Details ▾Hide ▴
Reasoning

PP4 is designated Not Applicable by the PALB2 VCEP specification.

VCEP rule
PALB2 VCEP v1.2: PP4 Not Applicable.
Evidence considered
  • The governing PALB2 VCEP v1.2 specification marks PP4 as Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates PP5 as not applicable. Details ▾Hide ▴
Reasoning

PP5 is designated Not Applicable by the PALB2 VCEP specification. Independently, ClinVar has no exact-variant expert-panel submission; its reported assertions are ordinary single-submitter laboratory or database submissions and cannot trigger PP5.

VCEP rule
PALB2 VCEP v1.2: PP5 Not Applicable; an exact-variant ClinVar Pathogenic/Likely pathogenic expert-panel assertion would otherwise be required.
Evidence considered
  • The governing PALB2 VCEP v1.2 specification marks PP5 as Not Applicable.
  • ClinVar variation 186811 is an exact match for c.829G>A/p.Asp277Asn, but the submission audit reports zero expert-panel submissions; the pathogenicity assertions shown are not expert-panel assertions.
Sources
cspec ↗clinvar ↗
BS3 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates BS3 as not applicable. Details ▾Hide ▴
Reasoning

The applicable PALB2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification, version 1.2, explicitly designates BS3 as Not Applicable. Therefore, BS3 cannot be assigned for this variant under the governing framework, regardless of the absence or presence of generic benign functional-assay evidence.

VCEP rule
ClinGen PALB2 VCEP Version 1.2: BS3 applicability = Not Applicable.
Evidence considered
  • The PALB2 VCEP specification is the governing framework and lists BS3 as Not Applicable.
  • The ACMG/AMP standards paper was consulted for general principles that functional evidence should come from biologically relevant, validated, reproducible, and robust assays; it reports no PALB2-specific assay or result for NM_024675.4:c.829G>A (NP_078951.2:p.(Asp277Asn)).
Still missing
  • No variant-specific validated functional assay result demonstrating a benign effect is available in the case evidence bundle; however, this gap does not change the VCEP-defined Not Applicable disposition.
Sources
cspec ↗PMID:25741868 ↗
BP2 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates BP2 as not applicable. Details ▾Hide ▴
Reasoning

The PALB2 VCEP Version 1.2 framework specifies BP2 as not applicable for PALB2. Consequently, the generic BP2 concept of an observation in trans with a pathogenic variant or in cis with a pathogenic variant is not used for this gene-specific assessment.

VCEP rule
PALB2 VCEP BP2: not applicable.
Evidence considered
  • The PALB2 VCEP Version 1.2 specification labels BP2 not applicable and provides no usable strength rule for it.
Sources
cspec ↗
BP3 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates BP3 as not applicable. Details ▾Hide ▴
Reasoning

BP3 is explicitly designated Not Applicable in the PALB2 VCEP specification. The assessed variant is a missense substitution, not an in-frame insertion/deletion; therefore repeat-region context cannot support BP3 for this variant.

VCEP rule
PALB2 VCEP BP3: Not Applicable.
Evidence considered
  • The PALB2 VCEP specification (version 1.2) lists BP3 as Not Applicable.
  • Variant normalization identifies the consequence as NP_078951.2:p.(Asp277Asn), not an in-frame insertion/deletion.
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates BP5 as not applicable. Details ▾Hide ▴
Reasoning

BP5 is designated Not Applicable by the PALB2 VCEP specification.

VCEP rule
PALB2 VCEP v1.2: BP5 Not Applicable.
Evidence considered
  • The governing PALB2 VCEP v1.2 specification marks BP5 as Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 expert panel specification (v1.2) designates BP6 as not applicable. Details ▾Hide ▴
Reasoning

BP6 is designated Not Applicable by the PALB2 VCEP specification. Independently, ClinVar has no exact-variant expert-panel submission; its Benign/Likely benign assertions are ordinary single-submitter laboratory submissions and cannot trigger BP6.

VCEP rule
PALB2 VCEP v1.2: BP6 Not Applicable; an exact-variant ClinVar Benign/Likely benign expert-panel assertion would otherwise be required.
Evidence considered
  • The governing PALB2 VCEP v1.2 specification marks BP6 as Not Applicable.
  • ClinVar variation 186811 is an exact match for c.829G>A/p.Asp277Asn, but the submission audit reports zero expert-panel submissions; its Benign/Likely benign assertions are therefore insufficient for BP6.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: BP7 requires a synonymous or deep-intronic variant, and this is a missense change. Details ▾Hide ▴
Reasoning

NM_024675.4:c.829G>A is a missense variant, p.(Asp277Asn), rather than a synonymous or deep-intronic variant. It therefore does not meet the PALB2 VCEP applicability conditions for BP7 or BP7(RNA).

Rule
PALB2 VCEP BP7: synonymous/deep-intronic variants only; BP7(RNA) is for an observed lack of aberrant RNA defect in silent or intronic variants.
Evidence considered
  • PALB2 VCEP BP7 applies to synonymous variants and deep-intronic variants beyond +7 at donor sites or -21 at acceptor sites; BP7(RNA) requires observed lack of aberrant RNA splicing for silent or intronic variants.
  • The normalized consequence is p.(Asp277Asn), a missense change.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.829G>A
Protein (HGVS p.)
NP_078951.2:p.(Asp277Asn)
GRCh38
chr16:23635717 C>T
GRCh37
chr16:23647038 C>T
Location and type
Exon 4 · missense
ClinVar
186811
COSMIC
COSV55167240

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 13 / 1,613,948 alleles AF 8.05e-06 · 0 homozygotes · FAF 2.55e-05
gnomAD v2.1 6 / 282,808 alleles AF 2.12e-05 · 0 homozygotes · FAF 3.98e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 8.1e-06 · 13 / 1,613,948 alleles · 0 hom · FAF 2.6e-05
African/African American5 / 74,912 6.7e-05
Admixed American1 / 59,978 1.7e-05
European (non-Finnish)7 / 1,180,032 5.9e-06
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 2.1e-05 · 6 / 282,808 alleles · 0 hom · FAF 4e-05
African/African American2 / 24,960 8e-05
Admixed American1 / 35,440 2.8e-05
European (non-Finnish)3 / 129,132 2.3e-05
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.05478e-06; MAF= 0.00081%, 13/1613948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.6745e-05; MAF= 0.00667%, 5/74912 alleles, homozygotes = 0); grpmax FAF= 2.55e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.12158e-05; MAF= 0.00212%, 6/282808 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01282e-05; MAF= 0.00801%, 2/24960 alleles, homozygotes = 0); grpmax FAF= 3.98e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +436 bp
0.000
SpliceAI acceptor gainat -391 bp
0.000
SpliceAI donor lossat -29 bp
0.001
SpliceAI donor gainat +24 bp
0.002
Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.005

Other predictors

REVEL
0.006
BayesDel
-0.862

How the predictions were used

BP4 SupportingMet (Supporting): SpliceAI max delta 0.002 meets the <=0.1 threshold, indicating no predicted splice impact. Details ▾Hide ▴
Reasoning

The PALB2 VCEP directs splice analysis for all variant types and assigns BP4_Supporting when SpliceAI is <=0.1. This missense variant has a maximum SpliceAI delta of 0.002, meeting that calibrated splice-prediction threshold. BP4 is applied once through the splicing path; REVEL and BayesDel are not additionally counted.

Rule
PALB2 VCEP BP4_Supporting: apply for no predicted splice impact when SpliceAI <=0.1; use the splice path only, not missense protein predictors.
Evidence considered
  • PALB2 VCEP BP4: splice analysis must be considered for all variant types and BP4 is assigned for no predicted splice impact at SpliceAI <=0.1; the VCEP does not permit missense protein-predictor BP4 evidence for PALB2.
  • SpliceAI for NM_024675.4:c.829G>A reports a maximum delta score of 0.002, below the VCEP BP4 cutoff of 0.1.
  • REVEL 0.006 and BayesDel -0.862298 were not counted, preventing duplicate computational evidence and respecting the VCEP exclusion of PALB2 missense protein predictors; BayesDel lacks a verified calibrated threshold publication/table in this case.
Still missing
  • No variant-specific RNA splicing assay is provided; if a future assay demonstrates a substantial splice defect, re-adjudicate PP3/BP4 under the PALB2 VCEP RNA guidance.
Sources
cspec ↗spliceai ↗revelbayesdel
PP3 Not met: SpliceAI max delta 0.002 falls below the >=0.2 threshold required for PP3 splice evidence. Details ▾Hide ▴
Reasoning

The PALB2 VCEP specification restricts PP3 for missense variants to predicted splice impact and requires SpliceAI >=0.2. The observed maximum SpliceAI delta is 0.002, so the PP3 splice threshold is not met. Protein-level missense predictors are not used because this VCEP explicitly states that published predictors have not achieved functional outcome for PALB2 missense variants.

Rule
PALB2 VCEP PP3 (Supporting): for non-canonical splice variants, apply only when SpliceAI >=0.2; missense protein-predictor evidence is not used.
Evidence considered
  • PALB2 VCEP PP3: assess splice impact for all variant types; apply PP3 only for SpliceAI >=0.2, and do not use missense protein predictors because published predictors have not achieved functional outcome for PALB2 missense variants.
  • SpliceAI for NM_024675.4:c.829G>A reports DS_AG 0.000, DS_AL 0.000, DS_DG 0.002, DS_DL 0.001; maximum delta 0.002.
  • REVEL 0.006 and BayesDel -0.862298 were not used for PP3: the governing PALB2 VCEP excludes missense protein-predictor use, and no verified BayesDel calibration publication/table is available in this case.
Still missing
  • No variant-specific RNA splicing assay is provided; a future assay demonstrating a substantial splice defect would require re-adjudication under the PALB2 VCEP RNA guidance.
Sources
cspec ↗spliceai ↗revelbayesdel
BP7 N/ANot applicable: BP7 requires a synonymous or deep-intronic variant, and this is a missense change. Details ▾Hide ▴
Reasoning

NM_024675.4:c.829G>A is a missense variant, p.(Asp277Asn), rather than a synonymous or deep-intronic variant. It therefore does not meet the PALB2 VCEP applicability conditions for BP7 or BP7(RNA).

Rule
PALB2 VCEP BP7: synonymous/deep-intronic variants only; BP7(RNA) is for an observed lack of aberrant RNA defect in silent or intronic variants.
Evidence considered
  • PALB2 VCEP BP7 applies to synonymous variants and deep-intronic variants beyond +7 at donor sites or -21 at acceptor sites; BP7(RNA) requires observed lack of aberrant RNA splicing for silent or intronic variants.
  • The normalized consequence is p.(Asp277Asn), a missense change.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.006. BayesDel score = -0.862298.

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

  • ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making.
    No paper-specific finding is recorded.
    PMID 23012255 ↗
  • Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.
    No paper-specific finding is recorded.
    PMID 23852704 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    The paper provides general ACMG/AMP guidance for functional evidence and cautions that computational predictions should not be the sole basis for a clinical assertion. It does not mention PALB2 or NM_024675.4:c.829G>A (NP_078951.2:p.(Asp277Asn)) and reports no variant-specific functional assay.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    However these are only predictions, and their use in sequence variant interpretation should be used carefully. It is not recommended that these predictions be used as the sole source of evidence to make a clinical assertion.

    Computational (In Silico) Predictive Programs

  • Patterns and functional implications of rare germline variants across 12 cancer types.
    Lu C et al. · 2015
    No paper-specific finding is recorded.
    PMID 26689913 ↗
  • Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
    Decker B et al. · 2017
    This paper does not explicitly report PALB2 c.829G>A (NP_078951.2:p.(D277N)). At the gene level, it reports that rare missense variants within the PALB2 N-terminal BRCA1-binding domain were associated with breast cancer risk, with the signal driven by 29 rare missense variants between amino acids 70 and 300. This aggregate domain-level observation was considered during PM1 review but cannot override the applicable PALB2 VCEP designation of PM1 as not applicable.
    Does not name this variant
    PMID 28779002 ↗
    Quoted passage
    In PALB2, missense variants within the N-terminal BRCA1 binding domain were most strongly associated with risk (OR=1.76; 95% CI 1.03 to 2.98, p=0.047). This signal was driven by rare missense variants (n=29) between amino acids 70 and 300, and few of these were predicted by CADD, PolyPhen2, SIFT or AlignGVGD to have a deleterious effect on the protein (see online supplementary table S5).

    Results, section "Risk associations for subsets of missense variants"; Table 3 and supplementary table S5

  • Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.
    DeRycke MS et al. · 2017
    No paper-specific finding is recorded.
    PMID 28944238 ↗
  • BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.
    No paper-specific finding is recorded.
    PMID 20301425 ↗
  • RAS testing of colorectal carcinoma&#x2014;a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group.
    No paper-specific finding is recorded.
    PMID 24996433 ↗

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

gnomAD v4.1 13 / 1,613,948 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.002 Open source ↗
ClinVar 4 Uncertain significance · 2 Likely benign · 1 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= 8.05478e-06; MAF= 0.00081%, 13/1613948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.6745e-05; MAF= 0.00667%, 5/74912 alleles, homozygotes = 0); grpmax FAF= 2.55e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.12158e-05; MAF= 0.00212%, 6/282808 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01282e-05; MAF= 0.00801%, 2/24960 alleles, homozygotes = 0); grpmax FAF= 3.98e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 186811)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.006. BayesDel score = -0.862298.

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 previously been reported in somatic cancers (COSMIC; COSV55167240, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.