NM_133487.3:c.235C>T

RAD51 · NP_597994.3:p.(Arg79Cys) · NM_133487.3

GRCh37: chr15:40994013 C>T · GRCh38: chr15:40701815 C>T

Gene: RAD51 Transcript: NM_133487.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51

Transcript

NM_133487.3

Protein

NP_597994.3:p.(Arg79Cys)

gnomAD AF

0.00016675079319296223 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_133487.3:c.235C>T (p.Arg79Cys) is a rare missense variant in RAD51, present at very low frequency in gnomAD (v2.1: 0.018%; v4.1: 0.017%) with no homozygotes observed, meeting PM2 at supporting level.

Multiple in silico prediction tools (REVEL 0.025, BayesDel -0.556, SpliceAI max delta 0.07) do not support a deleterious effect, meeting BP4 at supporting level.

The variant is absent from ClinVar and has not been reported in the germline literature. No functional studies, segregation data, case-control comparisons, or de novo observations are available.

Residue Arg79 is located in the N-terminal domain, outside the functionally critical RecA-like ATPase core (Walker A/B motifs), and is not in a statistically significant mutational hotspot.

Applying the generic ACMG/AMP 2015 final combination rules (PMID:25741868), the evidence comprises one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). These are insufficient to reach a classification of Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant is classified as a 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	NM_133487.3:c.235C>T is a missense variant (p.Arg79Cys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No known pathogenic variant at the same nucleotide position (c.235) was identified for comparison. ClinVar is absent for this variant and no alternative nucleotide change at this position was found in the evidence sources.	clinvar
PS2	Not assessed	No de novo evidence is available for NM_133487.3:c.235C>T. Neither ClinVar nor the literature search identified any report of this variant occurring de novo with confirmed maternity and paternity.	clinvar
PS3	Not assessed	No variant-specific functional studies were identified for NM_133487.3:c.235C>T (p.Arg79Cys). OncoKB reports Unknown Oncogenic Effect with no variant-level reviewed functional evidence. No literature publications with functional characterization of this variant were found.	oncokb clinvar
PS4	Not assessed	No case-control studies or disease-specific cohort data are available for NM_133487.3:c.235C>T. The variant is absent from ClinVar and no publications reporting case-control comparisons were identified.	clinvar
PS5	N/A	No reputable source has classified NM_133487.3:c.235C>T as pathogenic. The variant is absent from ClinVar entirely.	clinvar
PM1	Not met	Codon 79 (p.Arg79) is located in the N-terminal region of RAD51, outside the RecA-like ATPase domain that contains the functionally critical Walker A and Walker B motifs. Cancer Hotspots analysis confirmed that this residue is not in a statistically significant mutational hotspot.	oncokb
PM2	Met	NM_133487.3:c.235C>T is present at very low frequency in gnomAD population databases: v2.1 AF = 0.01847% (9/48,718 alleles) and v4.1 AF = 0.01668% (37/221,888 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada in the adjusted call set. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	No known pathogenic missense variant at the same residue (Arg79) was identified. PM5 candidate harvesting was unable to establish classic same-residue pathogenicity semantics for this variant.	pm5_candidates clinvar
PM6	Not assessed	No de novo evidence is available for NM_133487.3:c.235C>T. Neither ClinVar nor the literature search identified any report of this variant as a de novo occurrence.	clinvar
PP1	Not assessed	No co-segregation data are available for NM_133487.3:c.235C>T. No family studies reporting segregation of this variant with disease were identified in the literature or ClinVar.	clinvar
PP2	Not assessed	Insufficient gene-level constraint data are available to evaluate whether RAD51 has a low rate of benign missense variation. No Z-score, Missense Constraint (Mis-Z), or other constraint metrics were retrieved for this gene in the evidence pipeline.
PP3	Not met	Multiple in silico prediction tools do not support a deleterious effect for NM_133487.3:c.235C>T (p.Arg79Cys). REVEL score is 0.025 (well below the typical supporting threshold of 0.5), BayesDel score is -0.556 (negative; benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.07).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history information is available for NM_133487.3:c.235C>T. The variant has not been reported in a clinical context in ClinVar or the literature.	clinvar
PP5	N/A	No reputable source has classified NM_133487.3:c.235C>T as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The highest population allele frequency for NM_133487.3:c.235C>T is 0.0939% in the Admixed American population (gnomAD v2.1), which does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The highest population allele frequency for NM_133487.3:c.235C>T is 0.0939% in the Admixed American population (gnomAD v2.1), which does not exceed the 0.3% BS1 threshold for non-VCEP adjudication.	gnomad_v2 gnomad_v4
BS2	Not assessed	No clinical data on healthy adult carriers of NM_133487.3:c.235C>T are available. No homozygous or hemizygous observations have been reported in population databases or clinical sources.	gnomad_v2 gnomad_v4
BS3	Not assessed	No variant-specific functional studies were identified for NM_133487.3:c.235C>T (p.Arg79Cys). No in vitro or in vivo assays demonstrating a neutral functional effect are available.	oncokb
BS4	Not assessed	No segregation data are available for NM_133487.3:c.235C>T. No family studies demonstrating lack of co-segregation with disease were identified.	clinvar
BP1	Not met	While loss-of-function is an established disease mechanism for RAD51, missense variants are also reported in RAD51-associated disease. The gene does not have a predominantly truncating disease mechanism; both missense and truncating variants are implicated in RAD51-related phenotypes.	pvs1_gene_context
BP2	Not assessed	No phase information is available for NM_133487.3:c.235C>T. No observations in trans or cis with known pathogenic variants have been reported in ClinVar or the literature.	clinvar
BP4	Met	Multiple in silico prediction tools suggest NM_133487.3:c.235C>T (p.Arg79Cys) has no deleterious effect. REVEL score is 0.025 (strongly benign-leaning), BayesDel score is -0.556 (negative; consistent with benign), and SpliceAI predicts no splicing impact (max delta 0.07).	revel bayesdel spliceai
BP5	Not assessed	No clinical data on alternative molecular diagnoses are available for carriers of NM_133487.3:c.235C>T. The variant has not been reported in cases with an alternate molecular basis for disease.	clinvar
BP6	N/A	No reputable source has classified NM_133487.3:c.235C>T as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_133487.3:c.235C>T is a missense variant (p.Arg79Cys), not a synonymous/intronic variant. BP7 applies exclusively to synonymous variants without predicted splice impact.
BP3	N/A	NM_133487.3:c.235C>T is a missense substitution, not an in-frame indel. BP3 applies to in-frame deletions/insertions in non-repeat regions.
PM3	N/A	No phase information or observations in trans with pathogenic variants are available for NM_133487.3:c.235C>T. PM3 assessment requires phase-resolved data not present in this case.	clinvar
PM4	N/A	NM_133487.3:c.235C>T is a missense substitution, not a non-frame-shifting insertion/deletion or stop-loss variant. PM4 applies to protein-length-altering changes outside of stop-loss.

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