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

PM1 supporting PM2 supporting PP3 supporting

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

PM1_Supporting: The variant alters Gly153, located within the Walker A motif (GAPGVGKT) of the RAD51C ATPase domain, a critical functional domain where pathogenic missense variants cluster and benign variation is absent in population databases.

2

PM2_Supporting: The variant is extremely rare in population databases (gnomAD v2.1 AF=7.95e-06, 2/251,462 alleles; gnomAD v4.1 AF=1.86e-06, 3/1,614,194 alleles; both well below the PM2 threshold of <0.1%).

3

PP3_Supporting: Multiple computational tools predict a deleterious effect. REVEL score is 0.635. Both SIFT and PolyPhen predicted G153D as likely pathogenic based on sequence conservation (PMID:21980511).

4

PS3 not assessed: Functional studies (PMID:37253112, PMID:36099300, PMID:39299233) describe deleterious effects for variants in the Walker A/ATP-binding region where Gly153 resides, but the abstracts do not confirm that p.Gly153Asp was among the specific variants tested and shown to be functionally deleterious. Full-text review of these papers is required to determine PS3 applicability.

5

The variant was identified in germline DNA of BRCA-negative breast and/or ovarian cancer cases in Clague et al. (PMID:21980511), which screened 286 high-risk families and found G153D among six non-synonymous variants. No truncating mutations were identified in this cohort.

6

In ClinVar (Variation ID 185444), the majority classification is Uncertain significance (7 clinical laboratories), while three laboratories classify as Likely pathogenic and one as Pathogenic (LOVD, no criteria provided). No ClinGen expert panel review is available.

7

Overall assessment: 3 supporting pathogenic criteria met (PM1_Supporting, PM2_Supporting, PP3_Supporting). Per ACMG/AMP 2015 combination rules, a minimum of 2 moderate or 1 moderate + 2 supporting criteria is needed for Likely pathogenic. With only 3 supporting criteria, the classification remains Variant of Uncertain Significance. PS3 assessment (pending full-text review of functional studies) could potentially elevate the classification to Likely pathogenic if moderate-level functional evidence is confirmed.

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	NM_058216.3:c.458G>A is a missense variant (p.Gly153Asp). It does not fall into the default null-variant buckets of nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or single/multi-exon deletion. The generic PVS1 framework (PMC6185798) confirms variant_bucket is 'other' and the framework is not applicable.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	N/A	No different nucleotide change at codon 153 resulting in the same amino acid substitution (p.Gly153Asp) has been described. The variant is c.458G>A (GGT>GAT); no alternative nucleotide change (e.g., c.458_459delinsX) causing the same p.Gly153Asp is known.
PS2	Not assessed	No de novo evidence identified. No published trio data, ClinVar de novo submissions, or case reports documenting confirmed parentage with absence of the variant in both parents for RAD51C c.458G>A.	clinvar
PS3	Not assessed	Functional studies by Hu et al. (PMID:37253112, HDR assay of 173 RAD51C variants), Prakash et al. (PMID:36099300, >50 variants in Walker A region), and Olvera-León et al. (PMID:39299233, SGE of 9,188 variants) describe deleterious effects for variants in the Walker A/ATP-binding region where Gly153 is located. However, the abstracts do not explicitly confirm that p.Gly153Asp (G153D) was among the specific variants tested and found functionally deleterious. Full-text review of these papers is required to determine whether PS3 can be applied and at what strength.	PMID:37253112 PMID:36099300 PMID:39299233
PS4	Not met	The variant was identified in germline DNA of BRCA-negative breast and/or ovarian cancer cases in the Clague et al. cohort (PMID:21980511, 286 cases screened, G153D among 6 non-synonymous variants found). However, the publication does not report case counts per variant, and no formal case-control comparison with statistical enrichment (odds ratio) is available. Population frequency in gnomAD is extremely low (v2.1 AF=7.95e-06, v4.1 AF=1.86e-06), suggesting potential enrichment, but insufficient data to meet PS4 thresholds.	PMID:21980511 gnomad_v2 gnomad_v4
PS5	N/A	No different pathogenic missense change at codon 153 (Gly153) has been established. This criterion requires a different missense variant at the same residue that has been determined to be pathogenic.
PM1	Met	The variant alters Gly153, which lies within the Walker A motif (GAPGVGKT) of the ATPase domain of RAD51C. This is a well-characterized critical functional domain essential for ATP binding and hydrolysis, required for homologous recombination repair. Published functional studies (PMID:36099300, PMID:37253112) identify a cluster of pathogenic missense variants in and around the Walker A box. Population databases (gnomAD) show near-zero missense variation in this motif, supporting that benign variation is absent from this domain.	PMID:36099300 PMID:37253112 gnomad_v2 gnomad_v4 revel
PM2	Met	This variant is extremely rare in population databases. gnomAD v2.1: 2/251,462 alleles (AF=7.95e-06, 0.00080%), no homozygotes. gnomAD v4.1: 3/1,614,194 alleles (AF=1.86e-06, 0.00019%), no homozygotes. Absent from gnomAD-Canada v1.0. All frequencies are well below the PM2 threshold of <0.1% (0.001).	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants (different amino acid change at Gly153) were identified in ClinVar or other databases. The pm5_candidates.json confirms no candidates found. Classic PM5 semantics cannot be safely applied.	pm5_candidates
PM6	Not assessed	No de novo evidence identified with or without confirmed parentage. No published case reports, trio studies, or ClinVar submissions document a de novo occurrence of RAD51C c.458G>A.	clinvar
PP1	Not assessed	No published family segregation data for RAD51C c.458G>A. No co-segregation studies in affected family members are available in the literature reviewed.
PP2	N/A	RAD51C has a missense Z-score of 0.98 in gnomAD, indicating the gene is tolerant to missense variation. PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. The Z-score does not support PP2 applicability.	gnomad_v4
PP3	Met	Multiple lines of computational evidence suggest a deleterious effect. REVEL score is 0.635 (>0.5 threshold favoring pathogenicity). Per PMID:21980511, both SIFT and PolyPhen predicted p.Gly153Asp (G153D) to be likely pathogenic based on sequence conservation. BayesDel score is 0.233, falling in the indeterminate range (0.13-0.27). SpliceAI predicts no splicing impact (max delta=0.03). The preponderance of in silico evidence favors a deleterious effect, supporting PP3 at the supporting level.	revel bayesdel spliceai PMID:21980511
PP4	N/A	PP4 applies when the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. The HBOC phenotype associated with RAD51C is not specific to a single gene (shared with BRCA1, BRCA2, PALB2, RAD51D, BRIP1, etc.). No patient-specific phenotype data was provided.
PP5	Not met	While three clinical laboratories in ClinVar classify this variant as Likely pathogenic (LabCorp, Myriad Genetics, GeneDx), seven classify it as Uncertain significance, and one (LOVD) as Pathogenic without criteria provided. No expert panel has reviewed this variant. The majority classification is VUS, and there is no consensus for pathogenicity among reputable sources. PP5 is not met.	clinvar
BA1	Not met	The variant is not common in population databases. gnomAD v2.1 AF=7.95e-06; gnomAD v4.1 AF=1.86e-06. Both are far below the BA1 threshold of >1% (0.01).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is not common enough to meet BS1. gnomAD v2.1 AF=7.95e-06; gnomAD v4.1 AF=1.86e-06. Both are far below the BS1 threshold of >0.3% (0.003).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals observed in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes). No observation of the variant in healthy adult individuals documented in a manner meeting BS2. The variant has been observed in affected individuals (PMID:21980511).	gnomad_v2 gnomad_v4 PMID:21980511
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. The available evidence from PMID:37253112, PMID:36099300, and PMID:39299233 indicates that variants in the Walker A/ATP-binding region of RAD51C (where Gly153 resides) impair homologous recombination repair, disrupt paralog interactions, and are functionally deleterious. These findings contradict the benign functional evidence requirement for BS3.	PMID:37253112 PMID:36099300 PMID:39299233
BS4	Not met	No segregation data is available to demonstrate lack of co-segregation with disease in multiple affected family members. The criterion cannot be applied without segregation studies.
BP1	N/A	This is a missense variant (c.458G>A, p.Gly153Asp). BP1 applies to in-frame deletions/insertions in a repetitive region without a known function. Not applicable to missense substitutions.
BP2	Not met	No observation of this variant in trans with a known pathogenic RAD51C variant in a healthy individual, which is required for BP2 in a dominant disorder. No cis/trans phase data is available.
BP4	Not met	Multiple computational tools predict a deleterious effect. REVEL score 0.635 (>0.5 threshold for pathogenicity). SIFT and PolyPhen both predicted G153D as likely pathogenic (PMID:21980511). SpliceAI shows no splicing impact (max delta=0.03). The preponderance of evidence contradicts a benign computational prediction. BP4 is not met.	revel bayesdel spliceai PMID:21980511
BP5	Not met	This variant has been observed in association with disease. It was identified in germline DNA of BRCA-negative breast and/or ovarian cancer cases (PMID:21980511, 286 cases screened, G153D among identified variants). The variant is not found in a case with an alternate molecular basis for disease, which is required to apply BP5.	PMID:21980511
BP6	Not met	No reputable source classifies this variant as benign. ClinVar shows a majority of Uncertain significance classifications (7 labs), with three Likely pathogenic and one Pathogenic (no criteria). BP6 requires a reputable source to have classified the variant as benign.	clinvar
BP7	N/A	NM_058216.3:c.458G>A is a missense variant causing p.Gly153Asp. BP7 applies to synonymous (silent) variants and intronic variants outside of conserved splice consensus sequences. Not applicable to non-synonymous substitutions.	spliceai

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