NM_133509.4:c.476G>A

RAD51B · NP_598193.2:p.(Arg159His) · NM_133509.4

GRCh37: chr14:68352609 G>A · GRCh38: chr14:67885892 G>A

Gene: RAD51B Transcript: NM_133509.4

Final call

Likely Benign

BS1 supporting BP4 supporting BP6 supporting

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Arg159His)

gnomAD AF

0.00023873470605789316 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_133509.4:c.476G>A (p.Arg159His) in RAD51B is classified as Likely benign based on three supporting benign criteria per the generic ACMG/AMP 2015 framework (PMID:25741868). The generic ACMG combination rules require ≥2 supporting benign criteria for Likely benign classification.

The variant exceeds the 0.3% BS1 allele frequency threshold in the South Asian subpopulation (gnomAD v2.1 SAS AF = 0.358%, 109/30,430 alleles, 1 homozygote; gnomAD v4.1 SAS AF = 0.337%, 305/90,530 alleles, 3 homozygotes; grpmax FAF = 0.303%), indicating it is too common to be a highly penetrant pathogenic variant (BS1_supporting).

Multiple in silico tools predict a benign impact: REVEL score 0.385 (below 0.5 threshold), BayesDel score 0.129 (near-zero), and SpliceAI max delta 0.00 (no splice impact), meeting BP4_supporting.

ClinVar reports this variant as Likely benign from three clinical testing laboratories (Ambry Genetics, PreventionGenetics, NHLS; Variation ID 1678949), meeting BP6_supporting.

No pathogenic or likely pathogenic criteria were met. PVS1 does not apply to this missense variant. PS3/PS4 are not met due to absence of variant-specific functional or case-control data. PM2 is not met as the variant frequency exceeds 0.1% in the South Asian population. PP3 is not met because all in silico tools predict a benign effect. PP5 is not met as ClinVar reports Likely benign, not pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Not met	NM_133509.4:c.476G>A is a missense variant (p.Arg159His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) does not apply to missense substitutions in the 'other' variant bucket. Although RAD51B loss of function is a supported germline disease mechanism, this specific alteration does not meet PVS1 eligibility.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence that the same amino acid change (p.Arg159His) has been previously established as pathogenic via a different nucleotide change. No comparators identified in ClinVar or literature.
PS2	Not assessed	No de novo reports for NM_133509.4:c.476G>A were identified in ClinVar submissions, literature, or public databases.
PS3	Not met	No variant-specific functional evidence was identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional data. None of the reviewed publications reported functional studies on NM_133509.4:c.476G>A (p.Arg159His).	oncokb
PS4	Not met	No case-control or cohort studies reporting enrichment of NM_133509.4:c.476G>A in affected versus unaffected individuals were identified. The papers associated with this ClinVar entry are breast cancer screening guidelines, genetic testing policy statements, and BRCA1/BRCA2-focused studies that do not report RAD51B variant-specific prevalence data.
PS5	N/A	PS5 is not a criterion in the generic ACMG/AMP 2015 framework (PMID:25741868). Not applicable in generic_acmg mode.	generic_acmg_combination_rules
PM1	Not met	This variant (p.Arg159His) is not located in a statistically significant mutational hotspot and does not lie within a well-established critical functional domain with supporting literature evidence for missense constraint. Residue-level hotspot analysis returned negative.
PM2	Not met	This variant is present in gnomAD v2.1 at an overall allele frequency of 0.042% (118/281,876 alleles) and in the South Asian subpopulation at 0.358% (109/30,430 alleles), exceeding the PM2 threshold of <0.1%. One homozygote is observed in gnomAD v2.1 and three homozygotes in gnomAD v4.1 (total AF=0.024%, 384/1,608,480 alleles, SAS AF=0.337%). The variant is too common in population databases to support PM2 for a presumed dominant disorder.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic comparator variants (different amino acid change at p.Arg159) were identified. Automatic PM5 candidate harvesting was unable to confirm classic same-residue semantics.	pm5_candidates
PM6	Not assessed	No de novo evidence for NM_133509.4:c.476G>A was identified. Without confirmed parental testing, PM6 cannot be applied.
PP1	Not assessed	No segregation data for NM_133509.4:c.476G>A were identified in any reviewed publication or database.
PP2	Not assessed	PP2 requires a low rate of benign missense variation in the gene and missense variants as a common disease mechanism. RAD51B germline disease appears primarily driven by truncating/LoF variants (PMID:25600502). Without gene-level missense constraint metrics (e.g., gnomAD Z-score, missense depletion data), PP2 cannot be confidently applied.
PP3	Not met	Multiple in silico tools predict a benign impact for this variant. REVEL score is 0.385 (below the 0.5 damaging threshold), BayesDel score is 0.129 (low/near-zero), and SpliceAI predicts no splice impact (max delta score = 0.00). All computational lines of evidence argue against a damaging effect.	revel bayesdel spliceai
PP4	Not assessed	Patient-specific phenotype and family history data were not provided for this assessment. PP4 requires that the variant is identified in a patient whose phenotype or family history is highly specific for the gene-associated disease.
PP5	Not met	ClinVar reports this variant as Likely benign (3 clinical laboratories; ClinVar Variation ID 1678949), not pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic. The ClinVar consensus classification does not support PP5.	clinvar
BA1	Not met	The overall allele frequency in gnomAD v2.1 is 0.042% and in gnomAD v4.1 is 0.024%, both well below the BA1 threshold of >1%. The highest subpopulation frequency (South Asian) is 0.358%, which also does not reach the 1% BA1 cutoff.	gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the 0.3% allele frequency threshold for a presumed dominant disorder in the South Asian subpopulation. In gnomAD v2.1, the SAS AF is 0.358% (109/30,430 alleles) with 1 homozygote, and in gnomAD v4.1, the SAS AF is 0.337% (305/90,530 alleles) with 3 homozygotes. The grpmax filtering allele frequency is 0.303% (v2.1). The presence of homozygous individuals in a population database further supports that this variant is too common to be a highly penetrant pathogenic variant. Assessed at supporting strength rather than strong benign due to the population-specific nature of the elevated frequency.	gnomad_v2 gnomad_v4
BS2	Not assessed	While this variant is observed in population databases (gnomAD), BS2 requires observation in a healthy adult individual for a disorder expected to be fully penetrant at an early age. RAD51B-associated cancer predisposition has incomplete and age-dependent penetrance, making BS2 difficult to apply without specific clinical data on the homozygous individuals observed in gnomAD.
BS3	Not assessed	No functional studies specifically assessing the impact of NM_133509.4:c.476G>A (p.Arg159His) on RAD51B protein function were identified. OncoKB reports no variant-specific reviewed functional evidence.	oncokb
BS4	Not assessed	No segregation data for NM_133509.4:c.476G>A were identified in any reviewed publication. BS4 requires lack of segregation in affected family members.
BP1	Not assessed	BP1 requires that the gene has a disease mechanism primarily through truncating variants and that the specific missense variant is in a gene where missense changes are not a known cause of disease. While RAD51B germline disease is associated with truncating mutations (PMID:25600502), insufficient evidence is available to determine whether pathogenic missense variants are absent from or rare in RAD51B.
BP2	Not assessed	No data on observation of NM_133509.4:c.476G>A in trans with a known pathogenic RAD51B variant. BP2 is typically applied for recessive disorders.
BP4	Met	Multiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.385 (below the published 0.5 threshold for pathogenicity), BayesDel score 0.129 (near-zero, consistent with benign impact), and SpliceAI max delta score 0.00 (no predicted splice alteration). All available in silico tools agree on a benign prediction.	revel bayesdel spliceai
BP5	Not assessed	No data identifying an alternate molecular basis for disease in a case harboring NM_133509.4:c.476G>A was identified.
BP6	Met	This variant is classified as Likely benign in ClinVar (Variation ID 1678949) by three clinical laboratories: Ambry Genetics, PreventionGenetics (part of Exact Sciences), and the National Health Laboratory Service. While the review status is 'criteria provided, single submitter' and no expert panel review has been performed, the consensus from multiple clinical testing laboratories supports a benign interpretation.	clinvar
BP7	N/A	NM_133509.4:c.476G>A is a missense variant (p.Arg159His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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