Starting
Initialising…
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RAD51D
Final classification
VUS
RAD51D c.641C>T · p.Pro214Leu
RAD51D

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes), meeting PM2 at supporting strength.

Gene
RAD51D
Transcript
NM_002878.3
HGVS · transcript:coding
NM_002878.3:c.641C>T
Consequence
N/A
GRCh38
chr17:35103480 G>A
GRCh37
chr17:33430499 G>A
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2 BP4 VUS
RAD51D c.641C>T

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes), meeting PM2 at supporting strength.1 Multiple in silico tools predict no damaging effect: REVEL score 0.266, BayesDel score 0.181, and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.2 The variant has been reported in ClinVar as Uncertain significance by five clinical laboratories (Variation ID: 574602). No expert panel review or pathogenic/benign classification has been rendered.3 No variant-specific functional studies, cosegregation data, de novo observations, or case-control enrichment data are available. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.4 The opposing PM2 (supporting) and BP4 (supporting benign) criteria effectively cancel each other, yielding an evidence framework consistent with Uncertain significance.

PM2 + BP4 VUS
Gene diagram · NM_002878.3 · variants mapped to exon structure
RAD51D NM_002878.3
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
      This variant is present in gnomAD v4.1 (AF= 1.23909e-06; MAF= 0.00012%, 2/1614084 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6949e-06; MAF= 0.00017%, 2/1180012 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00012% · 2 / 1,614,084
      0 hom · FAF 2.8e-05%
      European (non-Finnish)
      2 / 1,180,012
      0.00017%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 574602)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.266. BayesDel score = 0.181497.
      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. RAD51D, a DNA repair protein, is infrequently altered in cancer.
      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.
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 2 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
      25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR