NM_058216.3:c.923C>G

RAD51C · NP_478123.1:p.(Ala308Gly) · NM_058216.3

GRCh37: chr17:56801419 C>G · GRCh38: chr17:58724058 C>G

Gene: RAD51C Transcript: NM_058216.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.(Ala308Gly)

gnomAD AF

4.959419549535922e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable: NM_058216.3:c.923C>G is a missense variant (p.Ala308Gly) and does not fall into a null-variant bucket (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or large genomic deletion).	pvs1_generic_framework
PS1	Not assessed	No known pathogenic variant at the same amino acid position (Ala308) with a different nucleotide change was identified in ClinVar or the literature. Unable to assess PS1 without a comparator.
PS2	Not assessed	No de novo observations were identified in ClinVar, literature, or de novo databases. Exploratory search confirmed absence of de novo reports for this variant.
PS3	Not met	No verified functional evidence demonstrates a damaging effect for this variant. The exploratory literature search identified one study (Ahlborn et al. 2021, PMID:33409066) that reportedly found wild-type-like activity, but full-text is not available for verification; even if taken at face value, the reported finding is neutral-to-benign, not damaging.
PS4	Not met	Insufficient case-control data to meet PS4. The exploratory search identified Sun et al. 2018 (PMID:30257646) reporting this variant in 1 of 1,090 breast cancer cases and 0 of 1,036 controls, but the paper is not available for full-text verification. Even if verified, the single observation does not achieve statistical significance required for PS4.
PS5	Not assessed	No alternate variant at the same nucleotide position with stronger evidence of pathogenicity was identified.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative). While p.Ala308 resides within the RecA domain (aa 1-376), RAD51C lacks a VCEP-defined or well-established critical functional domain specification for PM1 under generic ACMG/AMP rules.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not assessed	No same-residue pathogenic comparator variants were identified. PM5 candidate harvesting returned zero candidates at codon 308.
PM6	Not assessed	No de novo observations with confirmed maternity and paternity were identified for this variant.
PP1	Not assessed	No cosegregation data are available for this variant.
PP2	Not assessed	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). No constraint data or gene-level missense intolerance metric was available in the evidence to support this criterion.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.262 (below 0.5 damaging threshold), BayesDel score is -0.252908 (strongly in benign range), and SpliceAI max delta is 0.08 (no predicted splicing impact). All in silico tools consistently predict a benign or neutral effect.	revel bayesdel spliceai
PP4	Not assessed	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	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance (7 clinical laboratories) and Benign (1 clinical laboratory), all with single-submitter review status. No expert panel or practice guideline has asserted pathogenicity.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 1% threshold required for BA1.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 4.959e-06 (0.0005%), far below the 0.3% threshold required for BS1.	gnomad_v4
BS2	Not assessed	No data are available regarding the observation of this variant in healthy adults without disease to rule out a fully penetrant dominant disorder.
BS3	Not assessed	The exploratory literature search identified Ahlborn et al. 2021 (PMID:33409066) as reporting wild-type-like functional activity for p.Ala308Gly in homologous recombination, RAD51 foci formation, and MMC sensitivity assays. However, the full-text of this paper was not available for verification and the paper is not in the source registry. Without verified full-text confirming the assays are well-established and the variant is directly evaluated, BS3 cannot be applied.
BS4	Not assessed	No data are available regarding lack of segregation with disease or observation of this variant in trans with a known pathogenic RAD51C variant.
BP1	Not met	BP1 is not applicable to RAD51C. Both missense and truncating variants are established disease mechanisms in RAD51C (heterozygous for breast/ovarian cancer, biallelic for Fanconi anemia). The gene is not one where primarily truncating variants cause disease.	pvs1_gene_context
BP2	Not assessed	No observation of this variant in cis with a known pathogenic RAD51C variant has been reported.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No observation of this variant in an individual with an alternate molecular basis for disease has been reported.
BP6	Not met	No reputable source has classified this variant as benign with supporting evidence that is unavailable for review. The single Benign classification in ClinVar is from a single submitter without expert panel status and does not meet the BP6 threshold for a reputable source.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_058216.3:c.923C>G is a missense variant (p.Ala308Gly) and does not qualify.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a single-nucleotide missense substitution.
PM3	N/A	Skipped per instruction: trivially not applicable.
PM4	N/A	Skipped per instruction: trivially not applicable to a substitution variant.

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