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.
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-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
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 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at an extremely low allele frequency in gnomAD v4.1 (AF=0.000124%, 2/1,614,084 alleles, 0 homozygotes). Well below the 0.1% PM2 threshold for dominant disorders.
gnomAD v2.1: absentgnomAD v4.1: 2/1614
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.266 (below the 0.5 damaging threshold), BayesDel score is 0.181 (below common 0.2–0.3 damaging thresholds), and SpliceAI max delta is 0.00 (no predicted splice impact).
REVEL: 0.266 (benign-leaning)BayesDel: 0.181 (benign-leaning)SpliceAI max delta: 0.00 (no predicted splice impact)
Assessed · not applied
Pathogenic
PS1
No data available to determine whether a different nucleotide change at the same amino acid residue (Pro214) has been established as pathogenic.
PS2
No de novo observation with confirmed maternity and paternity is available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or cohort data comparing variant prevalence in affected individuals versus controls is available.
PM1
This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org, and no domain-level constraint or functional domain data specific to RAD51D missense constraint is available to support PM1 application.
PM6
No de novo observation (maternity/paternity unconfirmed) has been reported for this variant.
PP1
No cosegregation data with disease in families is available for this variant.
PP2
No HCI prior or other gene-level constraint metric is available for RAD51D (gene_not_supported in HCI prior lookup).
PP3
Multiple in silico tools do not support a deleterious effect.
PP4
No detailed clinical phenotype or family history data are available for the probands carrying this variant.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 1% BA1 threshold.
BS1
The maximum allele frequency (gnomAD v4.1 NFE: 0.00017%) is well below the 0.3% BS1 threshold.
BS2
No data on observation in healthy adult controls for a fully penetrant early-onset disorder.
BS3
No well-established functional studies demonstrating no damaging effect on protein function or splicing are available.
BS4
No segregation data demonstrating absence of cosegregation with disease is available.
BP1
RAD51D loss of function is an established disease mechanism, but missense variants can also be pathogenic via dominant-negative or hypomorphic effects.
BP2
No data on observation in trans with a known pathogenic variant in RAD51D.
BP5
No data on observation of this variant in cases with an alternative molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 4
PVS1 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
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%
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
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 574602)
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
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.
COSMIC
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
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