NM_058216.3:c.923C>G (p.Ala308Gly) is a missense variant in exon 7 of RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer and autosomal recessive Fanconi anemia. This variant is extremely rare in population databases: gnomAD v4.1 reports 8 of 1,613,092 alleles (AF=4.959e-06, 0 homozygotes), and gnomAD v2.1 reports 1 of 251,378 alleles (AF=3.978e-06). The variant is absent from gnomAD-Canada.1 Multiple in silico predictors consistently suggest a benign effect: REVEL score 0.262 (below damaging threshold), BayesDel -0.252908 (benign prediction), and SpliceAI max delta 0.08 (no splicing impact).2 ClinVar records this variant as Uncertain significance by 7 clinical laboratories and Benign by 1 laboratory (Variation ID 187133), all with single-submitter review status and no expert panel classification.3 No verified functional studies demonstrate a damaging effect. A functional study reportedly showing wild-type-like activity (PMID:33409066) could not be verified as full-text was unavailable. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting pathogenic) and BP4 (supporting benign) are met. All other criteria are either not met, not assessed, or not applicable. The net classification is Variant of Uncertain Significance (VUS).4
RAD51C
Final classification
VUS
RAD51C c.923C>G · p.Ala308Gly
RAD51C
NM_058216.3:c.923C>G (p.Ala308Gly) is a missense variant in exon 7 of RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer and autosomal recessive Fanconi anemia.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0 v1.0.0 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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
RAD51C c.923C>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
PMID:25741868 ↗generic_acmg_combination_rules
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. gnomAD v4.1 reports an allele frequency of 4.959e-06 (8/1,613,092 alleles; 0 homozygotes; grpmax FAF=5.281e-05), well below the 0.1% threshold for PM2. gnomAD v2.1 reports 1/251,378 alleles (AF=3.978e-06). Absent from gnomAD-Canada.
gnomAD v2.1: AF=3.978e-06 (1/251378 alleles0 homozygotes)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.262 (below damaging threshold), BayesDel score is -0.252908 (benign prediction), and SpliceAI max delta is 0.08 (no predicted splicing impact). The consensus of in silico predictors supports a benign effect.
REVEL: 0.262 (below 0.5 thresholdsuggesting no damaging effect)BayesDel: -0.252908 (benign prediction)
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant at the same amino acid position (Ala308) with a different nucleotide change was identified in ClinVar or the literature.
PS2
No de novo observations were identified in ClinVar, literature, or de novo databases.
PS3
No verified functional evidence demonstrates a damaging effect for this variant.
PS4
Insufficient case-control data to meet PS4.
PM1
This variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative).
PM5
No same-residue pathogenic comparator variants were identified.
PM6
No de novo observations with confirmed maternity and paternity were identified for this variant.
PP1
No cosegregation data are available for this variant.
PP2
While missense variants are a known disease mechanism in RAD51C, PP2 additionally requires demonstration that the gene has a low rate of benign missense variation (e.g., high missense Z-score).
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No specific phenotypic data are available for the individual(s) carrying this variant to assess whether the phenotype is highly specific for RAD51C-related disease.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 1% threshold required for BA1.
BS1
Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 0.3% threshold required for BS1.
BS2
No data are available regarding the observation of this variant in healthy adults without disease to rule out a fully penetrant dominant disorder.
BS3
The exploratory literature search identified Ahlborn et al.
BS4
No data are available regarding lack of segregation with disease or observation of this variant in trans with a known pathogenic RAD51C variant.
BP1
BP1 is not applicable to RAD51C.
BP2
No observation of this variant in cis with a known pathogenic RAD51C variant has been reported.
BP5
No observation of this variant in an individual with an alternate molecular basis for disease has been reported.
BP6
No reputable source has classified this variant as benign with supporting evidence that is unavailable for review.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.95942e-06; MAF= 0.00050%, 8/1613092 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000106829; MAF= 0.01068%, 8/74886 alleles, homozygotes = 0); grpmax FAF= 5.281e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15309e-05; MAF= 0.00615%, 1/16252 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,613,092
0 hom · FAF 0.0053%
0 hom · FAF 0.0053%
African/African American 8 / 74,886 |
0.011% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 251,378
0 hom
0 hom
African/African American 1 / 16,252 |
0.0062% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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 (7 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 187133)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.262. BayesDel score = -0.252908.
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. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106470523, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 6 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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
32832836 ↗
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.
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