LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-14
Case ID: NM_058216.3_c.458G_A_20260614_174536
Framework: ACMG/AMP 2015
Variant classification summary

NM_058216.3:c.458G>A

RAD51C  · NP_478123.1:p.(Gly153Asp)  · NM_058216.3
GRCh37: chr17:56774107 G>A  ·  GRCh38: chr17:58696746 G>A
Gene: RAD51C Transcript: NM_058216.3
Final call
VUS
PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD51C
Transcript
NM_058216.3
Protein
NP_478123.1:p.(Gly153Asp)
gnomAD AF
1.8585126694808678e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_058216.3:c.458G>A (p.Gly153Asp) is a missense variant in RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer (MONDO:0016248, MONDO:0016419) and autosomal recessive Fanconi anemia (MONDO:0019391).
2
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for RAD51C v1.0.0 provide no criteria-level modifications (criteria set is empty); generic ACMG/AMP 2015 criteria (PMID:25741868) were applied.
3
This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), meeting PM2 at supporting strength.
4
In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning) versus BayesDel score 0.233 (benign-leaning); SpliceAI predicts no splice impact (max delta 0.03). Neither PP3 nor BP4 is met.
5
ClinVar reports this variant as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories (VariationID 185444); no expert panel consensus exists. PP5 and BP6 are not met.
6
Functional studies of RAD51C missense variants have been published (PMID:36099300, PMID:37253112, PMID:39299233), including saturation genome editing covering >99.5% of coding SNVs (PMID:39299233). However, NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in available abstracts and full-text files were not available for verification. PS3 and BS3 remain not assessed pending full-text review.
7
No de novo reports, no segregation data, no case-control enrichment data, and no same-residue pathogenic comparator exist. All remaining assessed criteria (PS1, PS2, PS4, PM5, PM6, PP1, PP4, BS1, BS2, BS4, BP2, BP5) are not met.
8
With only PM2 (supporting) met and no benign criteria satisfied, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework. Definitive classification requires full-text functional data from PMID:39299233 (saturation genome editing) and/or PMID:37253112 (functional characterization of RAD51C missense 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.458G>A is a missense variant (p.Gly153Asp), not a null variant (nonsense, frameshift, canonical splice site ±1,2, initiation codon, or single/multi-exon deletion).
PS1 Not met No evidence of a different nucleotide change at codon 153 resulting in the same amino acid substitution (p.Gly153Asp) that has been previously classified as pathogenic.
PS2 Not met No de novo occurrence of NM_058216.3:c.458G>A has been reported in any database or publication reviewed.
PS3 Not assessed Functional studies of RAD51C missense variants exist (PMID:36099300, PMID:37253112, PMID:39299233) and the saturation genome editing study (PMID:39299233) tested >99.5% of all coding SNVs and would include p.Gly153Asp by design, but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable to verify the variant-specific functional result. Cannot apply PS3 without confirmed variant-level functional evidence.
PS4 Not met No case-control study demonstrating statistically significant enrichment of NM_058216.3:c.458G>A in affected individuals versus controls has been identified. The variant is extremely rare in population databases (gnomAD v2.1 AF 7.95e-6, v4.1 AF 1.86e-6), which precludes case-control analysis.
gnomad_v2 gnomad_v4
PS5 Not assessed PS5 requires compelling functional data from a reputable source showing a damaging effect, akin to PS3. As PS3 could not be assessed due to lack of variant-specific functional evidence in available abstracts, PS5 is also not assessed.
PM1 Not assessed p.Gly153Asp lies within the Rad51/RecA domain (residues ~30-300), but the ClinGen HBOP VCEP for RAD51C v1.0.0 provides no PM1 specification (criteria.json is empty). Without VCEP-defined critical domains with established absence of benign missense variation, PM1 cannot be applied generically.
PM2 Met NM_058216.3:c.458G>A is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. Absent from gnomAD-Canada v1.0.
gnomad_v2 gnomad_v4
PM5 Not met No pathogenic missense variant at the same amino acid residue (Gly153) has been identified as a comparator. Automated PM5 candidate harvesting found zero same-residue candidates.
PM6 Not met No de novo observation of NM_058216.3:c.458G>A (assumed or confirmed) has been reported.
PP1 Not met No cosegregation data are available for NM_058216.3:c.458G>A with breast or ovarian cancer in multiple affected family members.
PP2 Not assessed PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common disease mechanism. RAD51C has both pathogenic missense and truncating variants, but without gnomAD missense constraint metrics (Z-score, o/e ratio) or VCEP guidance, the benign missense variation rate cannot be determined for this assessment.
PP3 Not met In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning, >0.5 threshold) but BayesDel score 0.233 (benign-leaning, <0.27 threshold). SpliceAI predicts no splice impact (max delta 0.03). PP3 requires multiple lines of computational evidence supporting a deleterious effect; the conflicting predictions do not meet this threshold.
revel bayesdel spliceai
PP4 Not met No patient phenotype or family history data specific to NM_058216.3:c.458G>A are available to assess whether the clinical presentation is highly specific for RAD51C-related disease.
PP5 Not met ClinVar reports NM_058216.3:c.458G>A as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories. No expert panel classification exists. The predominant VUS classification and lack of expert consensus do not satisfy PP5, which requires a reputable source to have recently classified the variant as pathogenic with unavailable evidence.
clinvar
BA1 Not met Allele frequency in gnomAD v2.1 (7.95e-6) and v4.1 (1.86e-6) is far below the BA1 threshold of >1%.
gnomad_v2 gnomad_v4
BS1 Not met Allele frequency in gnomAD v2.1 (7.95e-6, 0.0008%) and v4.1 (1.86e-6, 0.00019%) is far below the BS1 threshold of >0.3%.
gnomad_v2 gnomad_v4
BS2 Not met NM_058216.3:c.458G>A has not been observed in a homozygous state in gnomAD (0 homozygotes in v2.1 and v4.1) and no compound heterozygous observations in healthy adults have been reported.
gnomad_v2 gnomad_v4
BS3 Not assessed Functional studies exist (PMID:36099300, PMID:37253112, PMID:39299233) but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable. Cannot confirm or exclude a benign functional effect without variant-specific evidence.
BS4 Not met No family segregation data are available. BS4 requires lack of segregation in affected family members — no such evidence exists for this variant.
BP1 N/A BP1 is not applicable — RAD51C is not a gene where primarily truncating variants cause disease. Both missense and truncating pathogenic variants are well-documented in RAD51C.
BP2 Not met No evidence that NM_058216.3:c.458G>A has been observed in trans with a known pathogenic RAD51C variant in a case of Fanconi anemia or other recessive disorder.
BP3 N/A BP3 is not applicable — this variant is a missense substitution, not an in-frame indel in a repetitive region without a known function.
BP4 Not met In silico predictions are conflicting: BayesDel score 0.233 (benign-leaning, <0.27 threshold) suggests no impact, but REVEL score 0.635 (damaging-leaning, >0.5 threshold) contradicts. BP4 requires multiple lines of computational evidence suggesting no impact on gene product; only one of two predictors supports a benign interpretation.
revel bayesdel spliceai
BP5 Not met No evidence that NM_058216.3:c.458G>A has been observed in a case with an alternate molecular basis for disease that would refute its pathogenicity.
BP6 Not met ClinVar does not report NM_058216.3:c.458G>A as benign. The variant is classified as VUS by 7 clinical laboratories and Likely pathogenic by 3. No reputable source classifies this variant as benign.
clinvar
BP7 N/A BP7 is not applicable — NM_058216.3:c.458G>A is a missense variant (p.Gly153Asp), not a synonymous variant with no predicted splice impact.
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