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PALB2
Final classification
Uncertain Significance - Conflicting Evidence
PALB2 c.2734T>G · p.Trp912Gly
PALB2

The PALB2 c.2734T>G (p.Trp912Gly) variant has not been observed in COSMIC and has been reported in ClinVar as Uncertain Significance, including expert-panel review.

Gene
PALB2
Transcript
NM_024675.3
HGVS · transcript:coding
NM_024675.3:c.2734T>G
Consequence
N/A
GRCh38
chr16:23626250 A>C
GRCh37
chr16:23637571 A>C
Basis Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting; maps to Uncertain Significance - Conflicting Evidence. ▾
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP1 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2 BP1 Uncertain Significance - Conflicting Evidence
PALB2 c.2734T>G

The PALB2 c.2734T>G (p.Trp912Gly) variant has not been observed in COSMIC and has been reported in ClinVar as Uncertain Significance, including expert-panel review.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency below the PALB2 PM2_Supporting threshold of 0.000333%.2 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, and although REVEL and BayesDel scores are available, the PALB2 expert-panel specification does not use missense computational predictors for PP3 or BP4.3

PM2 + BP1 → Uncertain Significance - Conflicting Evidence
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗
3 spliceai ↗revelbayesdelcspec ↗
Gene diagram · NM_024675.3 · variants mapped to exon structure
PALB2 NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 2498117)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.562. BayesDel score = 0.00991955.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      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.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 9 PMIDs not cited in assessment
      25741868 ↗ 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. CLINVAR
      31757951 ↗ Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. CLINVAR
      34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR
      18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR
      20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR
      24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR