LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-22
Case ID: NM_133509.3_c.481C_T_20260722_090016
Framework: ACMG/AMP 2015
Variant classification summary

NM_133509.3:c.481C>T

RAD51B  · NP_598193.2:p.(Pro161Ser)  · NM_133509.3
GRCh37: chr14:68352614 C>T  ·  GRCh38: chr14:67885897 C>T
Gene: RAD51B Transcript: NM_133509.3
Final call
Likely Benign
PM2 supporting BP1 supporting benign BP4 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD51B
Transcript
NM_133509.3
Protein
NP_598193.2:p.(Pro161Ser)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_133509.3:c.481C>T (p.Pro161Ser) is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength.
2
The variant is a missense change in RAD51B, a gene where the established disease mechanism is loss-of-function via truncating variants. Published germline RAD51B pathogenic variants are nonsense or splice-site mutations (PMID:25600502), and systematic screening of RAD51B found no pathogenic missense variants in breast cancer families (PMID:21533530). BP1 is met at supporting benign strength.
3
Multiple in silico tools predict a benign effect: REVEL score 0.289, BayesDel score -0.077, and SpliceAI max delta 0.11. BP4 is met at supporting benign strength.
4
The variant is absent from ClinVar; no classification or functional evidence exists for this variant in the literature. OncoKB reports unknown oncogenic effect, and COSMIC reports the variant in somatic cancers (n=2) without functional characterization.
5
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): with two supporting benign criteria (BP1, BP4) and one supporting pathogenic criterion (PM2), the evidence weighs in favor of a benign interpretation, meeting the threshold for Likely Benign.
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 N/A c.481C>T is a missense variant producing p.Pro161Ser. This does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).
pvs1_generic_framework
PS1 Not met No known pathogenic variant at codon 161 with the same amino acid change (p.Pro161Ser) has been identified. The variant is entirely absent from ClinVar.
clinvar
PS2 Not met No de novo evidence is available. No family-based or parent-of-origin studies report this variant as a confirmed de novo occurrence.
PS3 Not met No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect. REVEL (0.289) and BayesDel (-0.077) predict a benign effect. No published experimental data exist for p.Pro161Ser or a systematically characterized range that includes residue 161.
oncokb revel bayesdel
PS4 Not met No case-control or cohort prevalence data are available. Variant is absent from ClinVar and has not been reported in affected individuals in the curated literature.
clinvar gnomad_v2 gnomad_v4
PS5 Not met Variant is absent from ClinVar; no reputable source has classified NM_133509.3:c.481C>T as pathogenic.
clinvar
PM1 Not met Residue 161 (Pro) is not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional characterization data identifying this residue as critical was found in the case materials.
PM2 Met NM_133509.3:c.481C>T is absent from gnomAD v2.1 and gnomAD v4.1, meeting the generic ACMG PM2 threshold (allele frequency <0.1% in population databases).
gnomad_v2 gnomad_v4 gnomad_canada
PM5 Not met No pathogenic missense variant at codon 161 of RAD51B was identified in ClinVar. Automated PM5 candidate harvesting returned no same-codon comparator variants.
pm5_candidates clinvar
PM6 Not met No assumed de novo evidence is available. No reports of this variant occurring de novo without confirmed parentage.
PP1 Not met No co-segregation data are available. No family-based studies with this variant.
PP2 Not met RAD51B disease mechanism is loss-of-function via truncating variants; missense variation is not a well-established disease mechanism for this gene. Additionally, no missense constraint data (HCI prior not available for RAD51B) exists to support a low rate of benign missense variation.
pvs1_gene_context
PP3 Not met Multiple in silico tools predict a benign effect: REVEL score 0.289 (below 0.5 threshold), BayesDel score -0.077 (negative score indicates benign), SpliceAI max delta 0.11 (below 0.2 threshold). No computational evidence supports a deleterious effect.
revel bayesdel spliceai
PP4 Not met No patient phenotype or clinical history was provided. Cannot assess whether the phenotype is highly specific for RAD51B-related disease.
PP5 Not met The variant is absent from ClinVar. No reputable source has classified NM_133509.3:c.481C>T as pathogenic.
clinvar
BA1 Not met Variant is absent from gnomAD v2.1 and v4.1. Allele frequency does not exceed the 1% BA1 threshold in any population.
gnomad_v2 gnomad_v4
BS1 Not met Variant is absent from gnomAD. Population allele frequency does not exceed the 0.3% BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not met No data on observation in healthy adult controls or unaffected individuals are available.
BS3 Not met No well-established in vitro or in vivo functional studies demonstrate no damaging effect for p.Pro161Ser. While in silico tools predict benign, this alone does not satisfy BS3 which requires experimental functional evidence.
revel bayesdel
BS4 Not met No segregation data are available to demonstrate lack of co-segregation with disease in affected family members.
BP1 Met NM_133509.3:c.481C>T (p.Pro161Ser) is a missense variant in RAD51B, a gene for which the established disease mechanism is loss-of-function via truncating variants. The published literature documents germline nonsense and splice-site mutations as pathogenic, while missense variants are not a well-established disease mechanism for this gene (PMID:25600502, PMID:21533530).
pvs1_gene_context
BP2 Not met No phasing data are available. Cannot assess whether this variant has been observed in trans with a pathogenic variant in RAD51B.
BP4 Met Multiple lines of computational evidence predict no impact on gene product: REVEL score 0.289 (below 0.5 threshold), BayesDel score -0.077 (negative score indicates benign), and SpliceAI max delta score 0.11 (below 0.2 threshold, no predicted splice alteration).
revel bayesdel spliceai
BP5 Not met No information about an alternate molecular basis for disease in this case is available.
BP6 Not met The variant is absent from ClinVar. No reputable source has classified this variant as benign.
clinvar
BP7 N/A BP7 applies to synonymous (silent) variants. NM_133509.3:c.481C>T is a missense variant producing p.Pro161Ser.
BP3 N/A In-frame deletion/insertion criterion; this variant is a single-nucleotide substitution.
PM3 N/A Biallelic/recessive criterion; no phasing data available and RAD51B-related disease is not established as autosomal recessive.
PM4 N/A Protein length change criterion (non-repeat region); this variant is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss.
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