LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-27
Case ID: NM_133509.4_c.1111C_T_20260727_031414
Framework: ACMG/AMP 2015
Variant classification summary

NM_133509.4:c.1111C>T

RAD51B  · NP_598193.2:p.(Gln371Ter)  · NM_133509.4
GRCh37: chr14:69061276 C>T  ·  GRCh38: chr14:68594559 C>T
Gene: RAD51B Transcript: NM_133509.4
Final call
VUS
PVS1 moderate PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD51B
Transcript
NM_133509.4
Protein
NP_598193.2:p.(Gln371Ter)
gnomAD AF
4.531044451056413e-06 (v4.1)
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 of RAD51B. Loss of function is an established germline disease mechanism for RAD51B, supported by reports of truncating mutations in breast cancer, ovarian cancer, and melanoma families.
2
The premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids are truncated. Under the ClinGen SVI PVS1 framework (PMC6185798), a nonsense variant in the last exon with established LOF mechanism qualifies for PVS1 at moderate strength.
3
This variant is present at extremely low frequency in gnomAD v4.1 (AF = 4.53 × 10⁻⁶, 6/1,324,198 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, satisfying PM2 at supporting strength for a rare disease variant.
4
The variant is absent from ClinVar and has not been reported in any published case-control study. No variant-specific functional data or segregation data are available. The C-terminal tail (residues 371–384) has not been functionally characterized.
5
OncoKB classifies this variant as Likely Oncogenic with a predicted loss-of-function mechanism, consistent with the established role of RAD51B in homologous recombination repair. Gene-level functional studies demonstrate that RAD51B haploinsufficiency causes centrosome fragmentation, aneuploidy, and impaired homologous recombination.
6
Combined evidence: PVS1_Moderate + PM2_Supporting. No benign criteria are met. Using the ACMG/AMP 2015 combination rules, this classification reaches Likely Pathogenic.
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 Met NM_133509.4:c.1111C>T is a nonsense variant predicting p.(Gln371Ter) in exon 11 (the last coding exon) of RAD51B. Loss of function is an established disease mechanism for RAD51B, supported by germline literature identifying truncating mutations in breast cancer, ovarian cancer, and melanoma families. Under the ClinGen SVI PVS1 framework (PMC6185798), this variant is eligible for PVS1. However, the premature termination codon is in the last exon where nonsense-mediated decay is not predicted, and only 13 C-terminal amino acids (3.4% of the protein) are truncated. Per PMC6185798, nonsense variants in the last exon where NMD is not expected are assigned PVS1 at moderate strength.
pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:25600502
PS1 Not met No prior pathogenic classification exists for the same amino acid change p.(Gln371Ter). PS1 requires a previously classified pathogenic variant at the same residue. The variant is absent from ClinVar entirely.
clinvar
PS2 Not met No de novo testing data are available for this variant. PS2 requires confirmation of de novo occurrence with both maternity and paternity confirmed. No case-level data were provided.
PS3 Not met No variant-specific functional data exist for NM_133509.4:c.1111C>T (p.Gln371Ter). Five publications were reviewed in full text: PMID:16778173 (haploinsufficiency study using engineered RAD51B knockout in HCT116 cells), PMID:24139550 (first germline RAD51B truncating mutation c.452+3A>G), PMID:25368520 (siRNA knockdown in breast cancer cell lines), PMID:25600502 (germline RAD51B c.139C>T, p.Arg47* in melanoma family), and PMID:26261251 (population screening of RAD51B/C/D in ovarian cancer). None tested or reported the variant c.1111C>T / Q371*. The functional studies provide gene-level support for RAD51B LOF pathogenicity but do not satisfy PS3's requirement for variant-specific experimental data.
PS4 Not met Prevalence of this variant in affected individuals versus controls is unknown. The largest RAD51B case-control study (PMID:26261251) screened 3,429 ovarian cancer cases and 2,772 controls, identifying only two RAD51B deleterious mutations (G217X and Q219X), neither of which is this variant. No case-control data exist for NM_133509.4:c.1111C>T specifically.
PMID:26261251
PS5 Not met This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. No ClinVar variation ID was identified for NM_133509.4:c.1111C>T.
clinvar
PM1 Not met The variant lies at residue 371 in the extreme C-terminal tail of RAD51B (384 amino acids), truncating only 13 C-terminal residues. This region is not annotated as a critical functional domain. Cancerhotspots.org reports no statistically significant hotspot at this residue. No characterized functional domain (ATP-binding, RAD51C-interaction, or BCDX2 complex formation) is disrupted by this C-terminal truncation. The well-characterized functional domains of RAD51B (RAD51C interaction, ATP-binding) are N-terminal to this position.
PMID:16778173 PMID:26261251
PM2 Met This variant is present at an extremely low frequency in population databases. In gnomAD v4.1, it is observed at an allele frequency of 4.53 × 10⁻⁶ (6/1,324,198 alleles, 0 homozygotes), with the highest subpopulation frequency of 5.97 × 10⁻⁶ in the European (non-Finnish) population. The variant is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% PM2 threshold for a dominant disorder.
gnomad_v2 gnomad_v4 gnomad_canada
PM5 Not met PM5 applies when a different pathogenic missense change has been identified at the same amino acid residue. This variant is a nonsense change (p.Gln371Ter), and no pathogenic missense variant at codon 371 is present in ClinVar. The automated PM5 candidate search returned no comparator variants.
pm5_candidates clinvar
PM6 Not met No de novo occurrence data are available for this variant. PM6 requires observation of a de novo event without confirmation of paternity and maternity.
PP1 Not met No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2 N/A PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is a nonsense change, not a missense substitution.
PP3 N/A PP3 (multiple lines of computational evidence support a deleterious effect) is not independently applied to nonsense variants. The molecular consequence — a premature termination codon — already provides direct evidence of a deleterious effect, which is captured by PVS1. SpliceAI predicts no significant splice impact (max delta score = 0.09). REVEL score is not available. BayesDel score of 0.049 is low, reflecting that missense prediction tools are not calibrated for stop-gain variants.
spliceai bayesdel
PP4 Not met No patient phenotype data were provided for this case. PP4 requires that the proband phenotype or family history is highly specific for the disease entity associated with the gene.
PP5 Not met This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as pathogenic. The ClinVar search returned no matching variation IDs for NM_133509.4:c.1111C>T.
clinvar
BA1 Not met The gnomAD v4.1 allele frequency of 4.53 × 10⁻⁶ (0.00045%) is far below the 1% BA1 threshold. This variant is not a common polymorphism.
gnomad_v4
BS1 Not met The gnomAD v4.1 allele frequency of 4.53 × 10⁻⁶ (0.00045%) is far below the 0.3% BS1 threshold. Expected in a rare disease variant.
gnomad_v4
BS2 Not met No homozygotes are observed in gnomAD (0/1,324,198 alleles). BS2 requires observation in healthy adults in a homozygous or compound heterozygous state for a fully penetrant dominant disorder.
gnomad_v4
BS3 Not met No well-established functional studies showing no deleterious effect exist for this variant. None of the five full-text publications reviewed tested NM_133509.4:c.1111C>T. While gene-level functional studies (PMID:16778173, PMID:25368520) demonstrate RAD51B involvement in homologous recombination repair, these support a pathogenic role and do not provide benign effect evidence.
PMID:16778173 PMID:25368520
BS4 Not met No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members.
BP1 N/A BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is itself a truncating (nonsense) change in a gene where LOF is the established mechanism.
BP2 Not met No data are available regarding trans configuration with a known pathogenic RAD51B variant. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant in a recessive gene.
BP4 N/A BP4 (multiple lines of computational evidence suggest no impact) is not independently applied to nonsense variants that create a premature termination codon. The molecular consequence — loss of the C-terminal protein sequence and native stop codon — is inherently deleterious. SpliceAI predicts no cryptic splice effect (max delta = 0.09), but BP4 does not apply to truncating variants.
spliceai
BP5 Not met No alternative molecular basis for disease has been identified in this case, and BP5 is typically applied when an alternate cause is confirmed. Additionally, no benign ClinVar classification exists for this variant.
BP6 Not met The variant is absent from ClinVar; no reputable source has classified it as benign. BP6 requires a benign or likely benign classification from a reputable source.
clinvar
BP7 N/A BP7 applies to synonymous variants with no predicted splice impact. NM_133509.4:c.1111C>T is a nonsense (stop-gain) variant, not a synonymous substitution.
BP3 N/A Skipped per adjudication instructions (trivially not_applicable — in-frame indels in repeat regions). This variant is a single-nucleotide substitution.
PM3 N/A Skipped per adjudication instructions (trivially not_applicable — recessive disorder criterion for trans configuration; RAD51B-associated cancer predisposition follows autosomal dominant inheritance).
PM4 N/A Skipped per adjudication instructions (trivially not_applicable — PM4 applies to protein length changes from indels; this variant is a single-nucleotide substitution).
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