Starting
Initialising…
0%
PALB2
Final classification
Unclassified
PALB2 c.3549C>A · p.Tyr1183Ter
PALB2
Gene
PALB2
Transcript
NM_024675.3
HGVS · transcript:coding
NM_024675.3:c.3549C>A
Consequence
N/A
exon NC_000016.10
GRCh38
chr16:23603471 G>T
GRCh37
chr16:23614792 G>T
Classification rationale
Unclassified

No rationale recorded.

Gene diagram · NM_024675.3 · variants mapped to exon structure
PALB2 NM_024675.3
Fetching transcript structure from UCSC…
Applied criteria · 0 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
      This variant is present in gnomAD v4.1 (AF= 3.10151e-06; MAF= 0.00031%, 5/1612120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24356e-06; MAF= 0.00042%, 5/1178256 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 3.97741e-06; MAF= 0.00040%, 1/251420 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79306e-06; MAF= 0.00088%, 1/113726 alleles, homozygotes = 0).
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00031% · 5 / 1,612,120
      0 hom · FAF 0.00012%
      European (non-Finnish)
      5 / 1,178,256
      0.00042%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0004% · 1 / 251,420
      0 hom
      European (non-Finnish)
      1 / 113,726
      0.00088%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 128144)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant has previously been reported in somatic cancers (COSMIC; COSV104552896, n = 1 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      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
      18053174 ↗ Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. ONCOKB
      25529982 ↗ A novel PALB2 truncating mutation in an Italian family with male breast cancer. ONCOKB
      28279176 ↗ PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. ONCOKB
      28779002 ↗ Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. ONCOKB
      28858227 ↗ The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. ONCOKB
      29484706 ↗ Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes. ONCOKB
      17200671 ↗ Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. CLINVAR
      19264984 ↗ Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR