Classification rationale

PM2 BP4 VUS

RAD51C c.905-19T>C unknown · exon 6i

PM2 (Supporting): gnomAD allele frequency 0.0088% (v2.1) and 0.0057% (v4.1), both below the 0.1% rarity threshold. BP4 (Supporting): SpliceAI max delta 0.016, below the 0.1 threshold, indicating no predicted splicing impact. Variant of Uncertain Significance: PM2 (supporting pathogenic) and BP4 (supporting benign) oppose each other, satisfying no Benign, Likely Benign, Likely Pathogenic, or Pathogenic combination rule under ACMG/AMP 2015.

PM2 + BP4 → VUS

Gene diagram · NM_058216.3 · variants mapped to exon structure

RAD51C NM_058216.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): gnomAD allele frequency 0.0088% (v2.1) and 0.0057% (v4.1), both below the 0.1% PM2 rarity threshold.

gnomAD v2.1: 17/251,224 alleles (AF 0.006767%), grpmax FAF 0.008818%, with no homozygotes; the highest broad-population AF is 0.014085% in non-Finnish Europeans (16/113,594 alleles).gnomAD v4.1: 90/1,598,884 alleles (AF 0.005629%), grpmax FAF 0.005694%, with no homozygotes; the highest broad-population AF is 0.011292% in Remaining individuals (7/61,992 alleles).The variant is absent from gnomAD-Canada v1.0.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.016, below the <0.1 BP4 threshold, indicating no predicted splice impact.

SpliceAI max delta score = 0.016 (DS_AG=0.0, DS_AL=0.013, DS_DG=0.0, DS_DL=0.016), well below the 0.1 BP4 supporting threshold for intronic variants (source: spliceai).Generic ACMG/AMP in-silico calibration (output/generic_acmg_classification_rules.md, source basis PMID:25741868, SVI-recommended SpliceAI thresholds as also reflected in VCEP CSPEC specifications such as ATM's per Walker et al. 2023): SpliceAI max delta <0.1 -> BP4 supporting for intronic/synonymous/non-canonical splice-position variants.BayesDel score for this variant was retrieved (score present in prefetch data) but is not used for PP3/BP4 per this pipeline's policy: no verified published calibration threshold/PMID is available for BayesDel, so it is treated as not_available regardless of the raw score.

spliceai ↗

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no de novo observation or parental-testing data were available for this variant.

PS3 Not assessed: no validated functional assay data (splicing minigene, RT-PCR, or HDR assay) were available.

PS4 Not assessed: no case-control or statistical enrichment evidence for this variant was available.

PM3 Not assessed: no biallelic observation or second pathogenic/likely pathogenic RAD51C variant was reported.

PM6 Not assessed: no reported de novo occurrence or parental testing was available.

PP1 Not assessed: no segregation data from informative relatives were reported.

PP3 Not met: SpliceAI max delta 0.016, well below the >0.2 PP3 splice-path threshold.

PP4 Not assessed: no phenotype or personal/family cancer history was provided for the tested individual.

PP5 Not met: no ClinVar expert-panel pathogenic or likely pathogenic classification exists for this exact variant.

Benign

BA1 Not met: highest gnomAD allele frequency 0.0088%, far below the >1% BA1 stand-alone benign threshold.

BS1 Not met: highest observed gnomAD allele frequency 0.038% (NFE_SWE subset), below the >0.3% BS1 threshold.

BS2 Not met: gnomAD reports zero homozygotes and no disease-free carrier phenotype is established.

BS3 Not assessed: no validated functional assay with normal-range results was available.

BS4 Not assessed: no affected non-carrier or unaffected carrier observations were reported.

BP2 Not assessed: no co-occurrence data with a pathogenic RAD51C variant, or cis/trans phase, were reported.

BP5 Not assessed: no evidence of an alternative molecular diagnosis was available.

BP6 Not met: no ClinVar expert-panel benign or likely benign classification exists for this exact variant.

N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.62893e-05; MAF= 0.00563%, 90/1598884 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112918; MAF= 0.01129%, 7/61992 alleles, homozygotes = 0); grpmax FAF= 5.694e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.76687e-05; MAF= 0.00677%, 17/251224 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000140853; MAF= 0.01409%, 16/113594 alleles, homozygotes = 0); grpmax FAF= 8.818e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 90 / 1,598,884
0 hom · FAF 0.0057%

Remaining individuals 7 / 61,992	0.011%
European (non-Finnish) 81 / 1,166,312	0.0069%
European (Finnish) 2 / 64,014	0.0031%

+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0068% · 17 / 251,224
0 hom · FAF 0.0088%

European (non-Finnish) 16 / 113,594	0.014%
European (Finnish) 1 / 21,628	0.0046%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 492395)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 5 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

20301575 ↗ Fanconi Anemia. CLINVAR

25085752 ↗ Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. 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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR