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PALB2c.2135C>TBenign
Print report
Variant interpretation report

PALB2 c.2135C>T, p.(Ala712Val)

NM_024675.4:c.2135C>T NP_078951.2:p.(Ala712Val) Missense · exon 5 View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A 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 v1.3. 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: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BA1 threshold of >0.1%.

BS1Strong
BS1 · strong

Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BS1 threshold of >0.01%.

BP1Supporting
BP1 · supporting

Met, Supporting: BP1 applies to all missense variants, and NM_024675.4:c.2135C>T encodes missense p.Ala712Val.

Recorded classification: Benign

Benign: BA1 stand-alone benign independently satisfies PALB2 VCEP Rule17; BS1 (strong) and BP1 (supporting) are also met.

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
315 / 1,614,106 alleles

gnomAD v4.1: 315 / 1,614,106 alleles. Recorded AF 0.000195154. Recorded homozygote count 2.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000279264; MAF= 0.02793%, 79/282886 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.00138427; MAF= 0.13843%, 10/7224 alleles, homozygotes = 1); grpmax FAF= 0.00041893.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00027156202476645667, 5/18412 alleles, homozygotes = 0).

Applied · BA1, BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.041 recorded score

Recorded REVEL score: 0.041. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
22 reported laboratory submissions

16 Likely benign · 5 Benign · 1 benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99849032, n = 2 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 v1.3, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 2 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

For the requested consequence/LOF criteria, the variant is a missense SNV and the PALB2 VCEP explicitly marks PM4 and BP3 Not Applicable; PVS1 therefore does not apply.

PS2 and PM6 are explicitly not applicable under the PALB2 VCEP. PP1 and BS4 cannot be assessed because the available exact-variant evidence lacks validated segregation or non-segregation data and lacks LOD/LR statistics.

Among the requested criteria, PS4 cannot be assessed because available variant-specific reports do not provide the VCEP-required case-control statistics; PP4, PP5, BP5, and BP6 are explicitly not applicable under the PALB2 VCEP specification.

PP3 was evaluated only through the VCEP-named SpliceAI splicing path because the variant is missense; its maximum delta score of 0.028 is below the ≥0.2 PP3 threshold.

BP4 is not applicable because the VCEP explicitly excludes missense variants from BP4, including the splice-prediction path.

BP7 is not applicable because the VCEP limits it to synonymous or deep intronic variants and corresponding RNA evidence, not missense variants.

Met · 3

BA1 Stand aloneVCEPMet: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BA1 threshold of >0.1%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP version 1.3 rule assigns BA1 when the gnomAD grpmax Filtering AF is >0.1%. gnomAD v4.1 reports a grpmax FAF of 0.00412487 (0.412487%) for NM_024675.4:c.2135C>T (p.Ala712Val), which exceeds 0.1%; therefore BA1 is met at stand-alone strength.

VCEP rule
Grpmax Filtering AF **\>.1%** in gnomAD
Evidence considered
  • gnomAD v4.1 all-comers record for NM_024675.4:c.2135C>T / p.Ala712Val: grpmax FAF=0.00412487 (0.412487%), with the highest observed population frequency in Middle Eastern individuals at AF=0.00560871 (34/6062 alleles).
Sources
cspec ↗gnomad_v4 ↗
BS1 StrongVCEPMet: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BS1 threshold of >0.01%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP version 1.3 rule assigns BS1 when the gnomAD grpmax Filtering AF is >0.01%. gnomAD v4.1 reports a grpmax FAF of 0.00412487 (0.412487%) for NM_024675.4:c.2135C>T (p.Ala712Val), which exceeds 0.01%; therefore BS1 is met at strong strength.

VCEP rule
Grpmax Filtering AF **\>.01%** in gnomAD
Evidence considered
  • gnomAD v4.1 all-comers record for NM_024675.4:c.2135C>T / p.Ala712Val: grpmax FAF=0.00412487 (0.412487%), with the highest observed population frequency in Middle Eastern individuals at AF=0.00560871 (34/6062 alleles).
Sources
cspec ↗gnomad_v4 ↗
BP1 SupportingVCEPMet, Supporting: BP1 applies to all missense variants, and NM_024675.4:c.2135C>T encodes missense p.Ala712Val. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2135C>T (p.Ala712Val/p.A712V). The PALB2 VCEP BP1 rule states that BP1 applies to all missense variants; therefore BP1 is met at Supporting strength.

VCEP rule
Apply to all missense variants.
Evidence considered
  • PALB2 CSPEC BP1 rule: Apply to all missense variants.
  • The case evidence identifies NM_024675.4:c.2135C>T (p.Ala712Val/p.A712V) as a missense substitution.
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

PM2 VCEPNot met: the highest gnomAD v4.1 subpopulation AF is 0.560871%, above the VCEP PM2 threshold of 0.000333%. Details ▾Hide ▴
Reasoning

The PALB2 VCEP version 1.3 PM2 rule permits PM2 at supporting strength when frequency is ≤1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with a narrow exception for a single observation in one subpopulation only. gnomAD v4.1 reports the highest subpopulation AF as 0.00560871 (0.560871%) in Middle Eastern individuals, based on 34/6062 alleles and one homozygote; the variant is therefore far above the threshold and is present beyond a single observation, so PM2 is not met.

VCEP rule
Frequency ≤ 1/300,000 (**0.000333%**) in gnomAD subpopulation with the highest frequency Exception: If >0.000333% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2\_supporting would apply.
Evidence considered
  • gnomAD v4.1 all-comers record for NM_024675.4:c.2135C>T / p.Ala712Val: highest subpopulation AF=0.00560871 (0.560871%) in Middle Eastern individuals, 34/6062 alleles, with one homozygote; this is above 0.000333% and is not a single observation.
Sources
cspec ↗gnomad_v4 ↗
PP3 VCEPNot met: SpliceAI maximum delta score 0.028 is below the VCEP PP3 threshold of ≥0.2 for predicted splice impact. Details ▾Hide ▴
Reasoning

The VCEP excludes the missense-protein-prediction path but includes missense variants on its splicing path. SpliceAI is the predictor named by the VCEP, and the observed maximum delta score is 0.028 (reported as 0.03), below the VCEP PP3 threshold of ≥0.2; therefore the required predicted splice impact is absent and PP3 is not met. No protein predictor was used.

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
  • VCEP PP3 rule: missense protein prediction is not used, while the splicing path covers silent, missense/in-frame, and specified intronic variants and requires SpliceAI ≥0.2.
  • SpliceAI Lookup for NM_024675.4:c.2135C>T: DS_AG 0.028, DS_AL 0.001, DS_DG 0.001, DS_DL 0.007; maximum delta score 0.028 (displayed as 0.03).
Sources
cspec ↗spliceai ↗

Not assessed · 5 · no assessment recorded

PS4 VCEPNot assessed: the variant was reported in one cohort, but no VCEP-required case-control p-value, effect estimate, or confidence interval is available. Details ▾Hide ▴
Reasoning

The PALB2 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. The exact variant was observed in one Wilms-tumor cohort paper, but that paper reports no case-control p-value, effect estimate, or confidence interval for c.2135C>T; a separate population-based breast-cancer case-control study did not mention this variant. Therefore, the VCEP PS4 rule cannot be evaluated from the available variant-specific evidence.

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). No variant-specific values are available to substitute into these comparisons.
  • PMID:20589654, Table I, Missense Variants Identified in PALB2/FANCN, row c.2135C > T p.Ala712Val: the variant was identified in sample Rwt44 from a child with stage III mixed-histology Wilms tumor; the study was a 47-case cohort and did not report a variant-specific case-control p-value, effect estimate, or confidence interval.
  • PMID:22241545, Results paragraph 2 and Table 3: a population-based case-control study reported no specific rare missense mutation as significantly associated with breast-cancer risk, and the exact c.2135C>T/p.A712V variant was not mentioned.
Still missing
  • A variant-specific case-control study reporting p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is unavailable.
Sources
cspec ↗PMID:20589654 ↗PMID:22241545 ↗
PM3 VCEPNot assessed: the exact variant lacks documented Fanconi Anemia phenotype, pathogenic variant in trans, homozygosity, or phase information required by the VCEP PM3 table. Details ▾Hide ▴
Reasoning

The governing PALB2 VCEP PM3 rule requires a recessive-disease observation detected in trans with a pathogenic variant and directs use of the Fanconi Anemia PM3 tables. The required PALB2_PM3_BS2_1.3.pdf table was searched for c.2135C>T, p.Ala712Val, and p.A712V, with no matching row found. PMID:20589654 reports the exact variant in a child with Wilms tumor, but provides no Fanconi Anemia phenotype, pathogenic variant in trans, homozygosity, or phase information; therefore the VCEP PM3 points cannot be assigned.

VCEP rule
PM3 For recessive disorders, detected in trans with a pathogenic variant ... Phenotype consistent with PALB2-related FA
Evidence considered
  • PALB2_PM3_BS2_1.3.pdf: the variant was searched under c.2135C>T, p.Ala712Val, and p.A712V; no matching table row was found.
  • PMID:20589654, Table I, Missense Variants Identified in PALB2/FANCN: c.2135C>T (p.Ala712Val) was observed in sample Rwt44, a child with stage III mixed-histology Wilms tumor; the paper reports no functional assay, segregation analysis, population-frequency measurement, Fanconi Anemia phenotype, or phase with a pathogenic variant.
  • PMID:20589654, exact row: "c.2135C > T p.Ala712Val Unknown Benign Tolerated Less likely (C0) Presumably harmless Rwt44 18 III, mixed".
Still missing
  • No entry for c.2135C>T, p.Ala712Val, or p.A712V was found in PALB2_PM3_BS2_1.3.pdf.txt.
  • No documented Fanconi Anemia phenotype, pathogenic variant in trans, homozygosity, or phase information is available for this variant.
Sources
vcep_palb2_pm3_bs2_1_3 ↗PMID:20589654 ↗
PP1 VCEPNot assessed: the exact-variant report provides one proband but no affected relatives, parental testing, segregation count, LOD, or LR threshold value. Details ▾Hide ▴
Reasoning

The VCEP provides autosomal-dominant PP1 thresholds of LOD ≥1.26 or LR ≥18:1 for strong, LOD ≥0.60 or LR ≥4:1 for moderate, and LOD ≥0.3 or LR ≥2:1 for supporting evidence. The available exact-variant report identifies c.2135C>T (p.Ala712Val) in one Wilms tumor case but reports no segregation analysis, affected relatives, parental testing, meioses, LOD, or LR; therefore no PP1 strength can be assigned. A ClinVar submission signal mentioning a familial context is not a validated segregation dataset and does not provide the required count or likelihood statistic.

VCEP rule
AD Condition: LOD ≥1.26 or Bayes Factor (LR) ≥18:1; AD Condition: LOD ≥0.60 or Bayes Factor (LR) ≥4:1; AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1
Evidence considered
  • PALB2 VCEP CSPEC PP1 rule: AD strong requires LOD ≥1.26 or LR ≥18:1; moderate requires LOD ≥0.60 or LR ≥4:1; supporting requires LOD ≥0.3 or LR ≥2:1.
  • PMID:20589654, Table I, exact variant row: c.2135C>T (p.Ala712Val) was identified in sample Rwt44, a child with Wilms tumor; the paper reports no segregation analysis or parental testing.
  • A rejected, no-assertion-criteria ClinVar submission contains an incomplete familial-context signal but no auditable segregation count, parental results, meioses, LOD, or LR; it is not used to assign PP1.
Still missing
  • Validated segregation data in affected relatives
  • Parental genotypes and phase
  • Number of informative meioses
  • LOD or Bayes factor/LR
Sources
cspec ↗PMID:20589654 ↗
BS2 VCEPNot assessed: gnomAD reports homozygotes, but no Fanconi Anemia BS2 table points can be assigned without proband phenotype and age data. Details ▾Hide ▴
Reasoning

The PALB2 VCEP version 1.3 BS2 rule requires points assigned from the Fanconi Anemia BS2 table for probands, with strong BS2 requiring at least 4 points, moderate requiring 2 points, and supporting requiring 1 point. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.2135C>T, p.Ala712Val, and p.A712V, with no matching entry. The case evidence contains gnomAD homozygotes but does not provide the affected-status, age, phenotype, or proband-level information needed to assign BS2 table points; therefore BS2 is not assessed.

VCEP rule
BS2 **≥ 4** points See Fanconi Anemia BS2 tables for approach to assign points per proband.
Evidence considered
  • ClinGen PALB2 VCEP version 1.3 CSPEC BS2 entry: strong BS2 requires ≥4 points, moderate BS2 requires 2 points, and supporting BS2 requires 1 point; the rule directs use of the Fanconi Anemia BS2 tables.
  • PALB2_PM3_BS2_1.3.pdf was searched under c.2135C>T, p.Ala712Val, and p.A712V; no matching variant row was found.
  • gnomAD v4.1 reports total homozygotes=2 and one homozygote in the highest-frequency Middle Eastern population, but these population counts do not supply the VCEP BS2 table's proband phenotype and age inputs.
Still missing
  • No matching c.2135C>T, p.Ala712Val, or p.A712V entry was found in PALB2_PM3_BS2_1.3.pdf, the governing PM3/BS2 table file.
  • No proband-level Fanconi Anemia phenotype, affected status, age, zygosity, or phase data are available to calculate BS2 points.
Sources
cspec ↗vcep_palb2_pm3_bs2_1_3 ↗gnomad_v4 ↗
BS4 VCEPNot assessed: no non-segregating relatives, informative meioses, LOD, or LR are reported for comparison with the VCEP BS4 thresholds. Details ▾Hide ▴
Reasoning

The VCEP specifies BS4 using non-segregation likelihood thresholds: strong at LOD ≤ -1.28 or LR ≤.053:1, moderate at LOD ≤ -.64 or LR ≤.23, and supporting at LOD ≤-.32 or LR ≤.48. The available evidence contains no informative non-segregating relatives, unaffected tested relatives, number of meioses, LOD, or LR, so BS4 cannot be assessed.

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 thresholds: strong at LOD ≤ -1.28 or LR ≤.053:1, moderate at LOD ≤ -.64 or LR ≤.23, and supporting at LOD ≤-.32 or LR ≤.48.
  • No case source reports tested unaffected relatives, non-segregation observations, informative meioses, LOD, or LR for NM_024675.4:c.2135C>T (p.Ala712Val).
Still missing
  • Validated non-segregation observations
  • Phenotype and age data for tested unaffected relatives
  • Number of informative meioses
  • LOD or Bayes factor/LR
Sources
cspec ↗
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2135C>T produces the missense substitution p.Ala712Val, outside the PALB2 VCEP PVS1 null-variant scope. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. The case variant is NM_024675.4:c.2135C>T, NP_078951.2:p.(Ala712Val)/p.(A712V), a missense SNV in the clinically relevant PALB2 transcript. The PALB2 VCEP PVS1 rule is limited to null variants—nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, or single/multi-exon deletion—in a gene where loss of function is a known disease mechanism. This variant is not a null variant, does not alter protein length, and is not reported here as a splice defect; therefore NMD, exon importance, and repeat-region considerations do not create a PVS1 path. The governing PALB2_PVS1_v1.3.pdf file was searched for c.2135C>T, p.Ala712Val, and p.A712V; no variant-specific entry was 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
  • Variant-level assessment records NM_024675.4:c.2135C>T as consequence_class missense with protein consequence NP_078951.2:p.(Ala712Val)/p.(A712V).
  • The PALB2 VCEP PVS1 decision guide defines the applicable class as null variants: nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, or single/multi-exon deletion.
  • PALB2_PVS1_v1.3.pdf was searched for c.2135C>T, p.Ala712Val, and p.A712V with no matching variant-specific row or entry.
  • Fanconi anemia cohort paper Table I, row c.2135C > T / p.Ala712Val, reports this exact variant as a missense variant; its reported computational results were not used to infer any additional criterion.
Still missing
  • No variant-specific entry for c.2135C>T, p.Ala712Val, or p.A712V was found in PALB2_PVS1_v1.3.pdf; this is a file-search result, not evidence that the variant's consequence is absent from all sources.
Sources
cspec ↗pvs1_variant_assessmentvcep_palb2_pvs1_v1_3 ↗PMID:20589654 ↗
PS1 N/ANot applicable: PALB2 VCEP PS1 excludes missense changes, and the PS1 table has no c.2135C>T, p.Ala712Val, or p.A712V entry. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_024675.4:c.2135C>T (p.Ala712Val/p.A712V). The PALB2 VCEP PS1 guide explicitly excludes missense use because missense changes are not yet confirmed as a mechanism of disease for PALB2. The governing PALB2_PS1_1.3.pdf was searched for c.2135C>T, p.Ala712Val, and p.A712V; no entry for this variant was found.

VCEP rule
Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.
Evidence considered
  • VCEP PS1 rule: missense changes are excluded because missense changes are not yet confirmed as a mechanism of disease for PALB2.
  • Variant consequence in the case evidence: missense_variant; NM_024675.4:c.2135C>T corresponds to p.Ala712Val/p.A712V.
  • PALB2_PS1_1.3.pdf was searched under c.2135C>T, p.Ala712Val, and p.A712V; no matching variant row was found.
Still missing
  • No entry for this variant was found in PALB2_PS1_1.3.pdf after searching c.2135C>T, p.Ala712Val, and p.A712V.
Sources
cspec ↗vcep_palb2_ps1_1_3 ↗
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. No de novo evidence is therefore evaluated under this VCEP framework.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 VCEP CSPEC criterion entry: PS2 applicability is "Not Applicable."
Sources
cspec ↗
PS3 VCEPNot applicable: the PALB2 VCEP version 1.3 explicitly marks PS3 as not applicable, so no pathogenic functional-evidence strength is assigned. Details ▾Hide ▴
Reasoning

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP PALB2 version 1.3 specification marks PS3 as "Not applicable". Therefore, PS3 cannot be assigned for this PALB2 variant, regardless of whether functional assay evidence is available.

VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
  • ClinGen PALB2 VCEP version 1.3 CSPEC entry for PS3: applicability is "Not applicable"; its instruction states, "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion)."
Sources
cspec ↗
PM1 VCEPNot applicable: the PALB2 VCEP CSPEC explicitly marks PM1 as Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The PALB2 VCEP CSPEC marks PM1 as Not Applicable. No gene-specific domain_tables entry is present in vcep_materials.json, and the VCEP rule therefore does not permit PM1 for this variant.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 CSPEC criterion entry for PM1: applicability is Not Applicable.
  • vcep_materials.json domain_tables has no PALB2 entry.
Sources
cspec ↗
PM4 VCEPNot applicable: the PALB2 VCEP explicitly marks PM4 Not Applicable, and this variant is a protein-preserving missense SNV. Details ▾Hide ▴
Reasoning

PM4 is explicitly marked Not Applicable in the PALB2 VCEP CSPEC criteria for this framework. The variant is a missense SNV producing p.Ala712Val, with no protein-length change or in-frame insertion/deletion to evaluate under PM4. No generic PM4 rule was substituted.

VCEP rule
Not Applicable
Evidence considered
  • The PALB2 CSPEC entry for PM4 has applicability set to Not Applicable.
  • Variant-level assessment records c.2135C>T as a missense SNV with p.(Ala712Val), not an in-frame insertion/deletion or stop-loss change.
Sources
cspec ↗pvs1_variant_assessment
PM5 N/ANot applicable: PM5 is limited to NMD-prone truncating variants with PVS1 VeryStrong, whereas p.Ala712Val is missense. Details ▾Hide ▴
Reasoning

The variant is missense (p.Ala712Val). The PALB2 VCEP PM5 rule applies only to NMD-prone truncating DNA variants receiving PVS1 at VeryStrong with premature termination codons upstream of p.His1184, or the corresponding observed RNA-supported splice path. This missense variant is outside that applicability condition.

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 limits DNA-variant use to NMD-prone truncating variants receiving PVS1 at VeryStrong with premature termination codons upstream of p.His1184.
  • The case evidence identifies NM_024675.4:c.2135C>T (p.Ala712Val) as a missense SNV.
Sources
cspec ↗
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. No unconfirmed de novo evidence is therefore evaluated under this VCEP framework.

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

The PALB2 VCEP CSPEC marks PP2 as Not Applicable. No PP2 evidence may therefore be assigned under the governing PALB2 VCEP framework, regardless of the variant's missense consequence or gene-level mechanism.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 CSPEC criterion entry for PP2: applicability is Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for dominant PALB2 cancer predisposition because breast-cancer phenotypes are not sufficiently specific. Details ▾Hide ▴
Reasoning

The PALB2 VCEP does not permit PP4 for the autosomal-dominant PALB2 cancer-predisposition disorder because breast cancer is genetically heterogeneous and no phenotype features readily distinguish hereditary from sporadic causes.

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.
Evidence considered
  • The PALB2 VCEP states that PP4 must not be used for AD disease because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.
Sources
cspec ↗
PP5 VCEPNot applicable: the PALB2 VCEP explicitly prohibits PP5, regardless of available external pathogenicity assertions. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks PP5 as not applicable and explicitly instructs that this criterion is not for use. External pathogenicity assertions therefore cannot be converted into PP5 evidence under this VCEP.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PALB2 VCEP labels PP5 not applicable and states that 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, so no benign functional-evidence strength is assigned. Details ▾Hide ▴
Reasoning

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP PALB2 version 1.3 specification marks BS3 as "Not applicable". Therefore, BS3 cannot be assigned for this PALB2 variant, regardless of whether benign functional assay evidence is available.

VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
  • ClinGen PALB2 VCEP version 1.3 CSPEC entry for BS3: applicability is "Not applicable"; its instruction states, "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion)."
Sources
cspec ↗
BP2 VCEPNot applicable: the PALB2 Version 1.3 VCEP explicitly marks BP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The PALB2 Version 1.3 CSPEC entry marks BP2 as Not Applicable; no BP2 evaluation is permitted under the governing VCEP specification.

VCEP rule
Not Applicable
Evidence considered
  • PALB2 Version 1.3 CSPEC criterion entry for BP2: applicability is "Not Applicable".
Sources
cspec ↗
BP3 VCEPNot applicable: the PALB2 VCEP explicitly marks BP3 Not Applicable, and c.2135C>T is a missense SNV. Details ▾Hide ▴
Reasoning

BP3 is explicitly marked Not Applicable in the PALB2 VCEP CSPEC criteria for this framework. The variant is a missense SNV rather than an in-frame insertion/deletion in a repetitive region, and no generic BP3 rule was substituted.

VCEP rule
Not Applicable
Evidence considered
  • The PALB2 CSPEC entry for BP3 has applicability set to Not Applicable.
  • Variant-level assessment records c.2135C>T as a missense SNV producing p.(Ala712Val), not an in-frame insertion/deletion in a repetitive region.
Sources
cspec ↗pvs1_variant_assessment
BP4 N/ANot applicable: the VCEP BP4 rule excludes missense variants, including its splice-prediction path. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, c.2135C>T (p.Ala712Val). The VCEP BP4 rule explicitly says not to use the missense path and not to apply its splice-prediction path for missense variants; BP4 is therefore not applicable upstream of evaluating the 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
  • VCEP BP4 rule: missense variants are excluded, and the splicing path states not to apply it for missense variants; the case variant is NM_024675.4:c.2135C>T (p.Ala712Val).
Sources
cspec ↗
BP5 VCEPNot applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants do not reliably distinguish the phenotype in moderate-penetrance PALB2 disease. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP5 as not applicable and instructs that it must not be used because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2 has moderate penetrance.

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 PALB2 VCEP labels BP5 not applicable and states that cases with multiple pathogenic variants should not receive BP5.
Sources
cspec ↗
BP6 VCEPNot applicable: the PALB2 VCEP explicitly prohibits BP6, regardless of available external benign or likely-benign reports. Details ▾Hide ▴
Reasoning

The PALB2 VCEP marks BP6 as not applicable and explicitly instructs that this criterion is not for use. Available benign or likely-benign reports therefore cannot be converted into BP6 evidence under this VCEP.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The PALB2 VCEP labels BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited by the VCEP to synonymous or deep intronic variants, not this missense substitution. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, c.2135C>T (p.Ala712Val), whereas the VCEP BP7 rule applies to synonymous and deep intronic variants, or to RNA evidence concerning silent substitutions and intronic variants. This variant is outside BP7 scope, so BP7 is not applicable.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. ... * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • VCEP BP7 rule limits the computational path to synonymous and deep intronic variants and the RNA path to silent substitutions and intronic variants; the case variant is missense p.Ala712Val.
Sources
cspec ↗

Identifiers

Gene
PALB2
Transcript
NM_024675.4
Coding (HGVS c.)
NM_024675.4:c.2135C>T
Protein (HGVS p.)
NP_078951.2:p.(Ala712Val)
GRCh38
chr16:23630019 G>A
GRCh37
chr16:23641340 G>A
Location and type
Exon 5 · missense
ClinVar
126637
COSMIC
COSV99849032

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 v4.1 315 / 1,614,106 alleles AF 0.000195 · 2 homozygotes · FAF 0.00412
gnomAD v2.1 79 / 282,886 alleles AF 0.000279 · 1 homozygotes · FAF 0.000419
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0002 · 315 / 1,614,106 alleles · 2 hom · FAF 0.0041
Middle Eastern34 / 6,062 0.00561 hom
Ashkenazi Jewish33 / 29,604 0.0011
Remaining individuals27 / 62,508 0.00043
Admixed American24 / 60,016 0.0004
South Asian21 / 91,076 0.000231 hom
European (non-Finnish)174 / 1,180,012 0.00015
African/African American2 / 75,012 2.7e-05
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, East Asian.

gnomAD v2.1

AF 0.00028 · 79 / 282,886 alleles · 1 hom · FAF 0.00042
Remaining individuals10 / 7,224 0.00141 hom
Ashkenazi Jewish12 / 10,370 0.0012
Admixed American12 / 35,440 0.00034
European (non-Finnish)38 / 129,194 0.00029
South Asian7 / 30,616 0.00023
0 alternate alleles recorded in 3 other groups: African/African American, East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000195154; MAF= 0.01952%, 315/1614106 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00560871; MAF= 0.56087%, 34/6062 alleles, homozygotes = 1); grpmax FAF= 0.00412487.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000279264; MAF= 0.02793%, 79/282886 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.00138427; MAF= 0.13843%, 10/7224 alleles, homozygotes = 1); grpmax FAF= 0.00041893.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00027156202476645667, 5/18412 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +445 bp
0.001
SpliceAI acceptor gainat -60 bp
0.028
SpliceAI donor lossat -485 bp
0.007
SpliceAI donor gainat +409 bp
0.001
Pangolin splice lossmagnitude shown
-0.004
Pangolin splice gain
0.042

Other predictors

REVEL
0.041
BayesDel
-0.761

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta score 0.028 is below the VCEP PP3 threshold of ≥0.2 for predicted splice impact. Details ▾Hide ▴
Reasoning

The VCEP excludes the missense-protein-prediction path but includes missense variants on its splicing path. SpliceAI is the predictor named by the VCEP, and the observed maximum delta score is 0.028 (reported as 0.03), below the VCEP PP3 threshold of ≥0.2; therefore the required predicted splice impact is absent and PP3 is not met. No protein predictor was used.

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
  • VCEP PP3 rule: missense protein prediction is not used, while the splicing path covers silent, missense/in-frame, and specified intronic variants and requires SpliceAI ≥0.2.
  • SpliceAI Lookup for NM_024675.4:c.2135C>T: DS_AG 0.028, DS_AL 0.001, DS_DG 0.001, DS_DL 0.007; maximum delta score 0.028 (displayed as 0.03).
Sources
cspec ↗spliceai ↗
BP4 N/ANot applicable: the VCEP BP4 rule excludes missense variants, including its splice-prediction path. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, c.2135C>T (p.Ala712Val). The VCEP BP4 rule explicitly says not to use the missense path and not to apply its splice-prediction path for missense variants; BP4 is therefore not applicable upstream of evaluating the 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
  • VCEP BP4 rule: missense variants are excluded, and the splicing path states not to apply it for missense variants; the case variant is NM_024675.4:c.2135C>T (p.Ala712Val).
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited by the VCEP to synonymous or deep intronic variants, not this missense substitution. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, c.2135C>T (p.Ala712Val), whereas the VCEP BP7 rule applies to synonymous and deep intronic variants, or to RNA evidence concerning silent substitutions and intronic variants. This variant is outside BP7 scope, so BP7 is not applicable.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. ... * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • VCEP BP7 rule limits the computational path to synonymous and deep intronic variants and the RNA path to silent substitutions and intronic variants; the case variant is missense p.Ala712Val.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.041. BayesDel score = -0.761362.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
    Zhen DB et al. · 2015
    No paper-specific finding is recorded.
    PMID 25356972 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Fanconi anemia gene mutations are not involved in sporadic Wilms tumor.
    Adank MA et al. · 2010
    The exact PALB2 variant c.2135C>T (p.Ala712Val; NP_078951.2:p.(A712V)) was identified in germline DNA from sample Rwt44. The study reports computational predictions for the variant but no functional assay, segregation analysis, or population-frequency measurement.
    Names this variant
    PMID 20589654 ↗
    Quoted passage
    c.2135C > T p.Ala712Val Unknown Benign Tolerated Less likely (C0) Presumably harmless Rwt44 18 III, mixed

    Table I, Missense Variants Identified in PALB2/FANCN

  • Rare germline mutations in PALB2 and breast cancer risk: a population-based study.
    Tischkowitz M et al. · 2012
    This population-based case-control study did not explicitly mention PALB2 c.2135C>T or p.A712V. It reported that no specific rare missense mutation was significantly associated with breast-cancer risk, so it provides no variant-specific PS4 result for this case.
    Does not name this variant
    PMID 22241545 ↗
    Quoted passage
    Further analyses of the individual rare missense mutations using hierarchical modeling revealed no specific mutations as significantly associated with risk (data not shown).

    Results, paragraph 2; Table 3

  • Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.
    Pruss D et al. · 2014
    No paper-specific finding is recorded.
    PMID 25085752 ↗
  • Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
    No paper-specific finding is recorded.
    PMID 25980754 ↗
  • Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.
    No paper-specific finding is recorded.
    PMID 26283626 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    No paper-specific finding is recorded.
    PMID 26389210 ↗

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

gnomAD v4.1 315 / 1,614,106 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.028 Open source ↗
ClinVar 16 Likely benign · 5 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= 0.000195154; MAF= 0.01952%, 315/1614106 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.00560871; MAF= 0.56087%, 34/6062 alleles, homozygotes = 1); grpmax FAF= 0.00412487.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000279264; MAF= 0.02793%, 79/282886 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.00138427; MAF= 0.13843%, 10/7224 alleles, homozygotes = 1); grpmax FAF= 0.00041893.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00027156202476645667, 5/18412 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (16 clinical laboratories) and as Benign (5 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 126637)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.041. BayesDel score = -0.761362.

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; COSV99849032, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.