LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-23
Case ID: NM_133509.4_c.428C_T_20260723_170400
Framework: ACMG/AMP 2015
Variant classification summary

NM_133509.4:c.428C>T

RAD51B  · NP_598193.2:p.(Thr143Ile)  · NM_133509.4
GRCh37: chr14:68331832 C>T  ·  GRCh38: chr14:67865115 C>T
Gene: RAD51B Transcript: NM_133509.4
Final call
VUS
PM2 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD51B
Transcript
NM_133509.4
Protein
NP_598193.2:p.(Thr143Ile)
gnomAD AF
3.931872507473678e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
RAD51B c.428C>T (p.Thr143Ile) is observed at very low frequency in population databases (gnomAD v2.1: AF=0.0091%, 25/274,618 alleles; v4.1: AF=0.0039%, 63/1,602,290 alleles; no homozygotes), meeting PM2 at moderate strength.
2
This is a missense variant and does not qualify for PVS1 under the ClinGen SVI framework (PMC6185798), as it is not a nonsense, frameshift, or canonical splice site variant.
3
No variant-specific functional data, case-control studies, de novo observations, co-segregation data, or same-residue comparator variants were identified. In silico predictions are conflicting (REVEL 0.603, BayesDel 0.189, SpliceAI 0.01) and do not meet PP3 or BP4 thresholds.
4
ClinVar reports this variant as Uncertain significance (1★, single submitter: Ambry Genetics). No 3★ expert panel classification exists to support PP5 or BP6.
5
With only PM2 (moderate) met and all other criteria not met or not applicable, there is insufficient evidence to classify this variant beyond Uncertain Significance under ACMG/AMP 2015 rules (PMID:25741868). This is consistent with the ClinVar classification.
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 Not met This missense variant (p.Thr143Ile) does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense substitutions.
pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1 Not met No alternative nucleotide change at codon 143 producing the same amino acid substitution (Thr143Ile) was identified as pathogenic in ClinVar or the literature.
pm5_candidates
PS2 Not met No de novo observation with confirmed parentage reported for this variant.
PS3 Not met No variant-specific functional data identified. OncoKB reports unknown oncogenic effect with no cited PMIDs, COSMIC records one somatic occurrence (COSV108918756) but somatic presence alone does not constitute functional evidence for germline PS3.
oncokb
PS4 Not met The variant has been observed in general population databases (gnomAD, 25–63 alleles) without case-control comparison showing enrichment in affected individuals.
gnomad_v2 gnomad_v4
PS5 Not met No reputable source has recently reported this variant as pathogenic with inaccessible evidence.
clinvar
PM1 Not met Residue 143 does not fall within a statistically significant cancer hotspot (cancerhotspots.org) and no gene-specific literature establishes this position as a critical functional domain enriched for pathogenic missense variants. The nearby Walker A motif (residues ~128–135) is upstream; position 143 is outside the characterized ATP-binding domain.
PM2 Met This variant is present in gnomAD at very low frequency (v2.1: AF=0.0091%, 25/274,618 alleles; v4.1: AF=0.0039%, 63/1,602,290 alleles; highest subpopulation AF=0.062% in South Asian, v2.1), well below the 0.1% threshold for PM2 in non-VCEP context. No homozygotes observed.
gnomad_v2 gnomad_v4
PM5 Not met No pathogenic missense comparator variant at the same codon (position 143) was identified in ClinVar. Automated PM5 candidate search returned no candidates.
pm5_candidates
PM6 Not met No de novo observation reported for this variant (with or without confirmed parentage).
PP1 Not met No co-segregation data available for this variant in affected families.
PP2 Not met Insufficient evidence that RAD51B has a low rate of benign missense variation and that missense is a common mechanism of disease. RAD51B is a large gene where both truncating and missense variants occur; gene-level constraint data were not assessed in this evaluation.
PP3 Not met In silico predictions show conflicting results: REVEL score of 0.603 is moderately above the damaging threshold (0.5), but BayesDel score of 0.189 falls in the benign range (<0.27), and SpliceAI predicts no splicing impact (max delta=0.01). Multiple lines of computational evidence do not consistently support a deleterious effect, and therefore PP3 is not met.
revel bayesdel spliceai
PP4 Not met No proband phenotype or family history data are available to assess specificity for a RAD51B-associated disorder.
PP5 Not met ClinVar classification for this variant is Uncertain significance (1★, criteria provided, single submitter). PP5 requires a reputable source reporting the variant as pathogenic, and per global rule the ClinVar expert panel must be 3★ to qualify at supporting strength. Neither condition is met.
clinvar
BA1 Not met Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is well below the 1% BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is below the 0.3% BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not met No evidence that this variant has been observed in healthy adult individuals in a context permitting BS2 application (e.g., homozygous state or comprehensive healthy cohort data).
BS3 Not met No well-established functional studies demonstrating no damaging effect of this variant on protein function or splicing.
spliceai
BS4 Not met No family segregation data available to demonstrate lack of co-segregation with disease.
BP1 Not met RAD51B is a homologous recombination repair gene where both truncating and missense variants are reported in the literature. While germline truncating variants have been described (PMID:25600502), there is insufficient evidence that RAD51B disease is primarily mediated by truncating variants to apply BP1 to this missense change.
pvs1_gene_context
BP2 Not met No evidence that this variant has been observed in trans with a known pathogenic variant in RAD51B or another gene for a fully penetrant dominant disorder.
BP3 N/A In-frame indels only; this is a substitution variant.
BP4 Not met Multiple lines of computational evidence do not consistently support a benign effect. While BayesDel (0.189) falls in the benign range and SpliceAI (0.01) predicts no splicing impact, REVEL (0.603) predicts a damaging effect. Conflicting in silico predictions preclude application of BP4.
revel bayesdel spliceai
BP5 Not met No alternate molecular basis for disease has been identified in an individual carrying this variant.
BP6 Not met ClinVar classification for this variant is Uncertain significance (1★), not benign or likely benign. BP6 requires a reputable source reporting the variant as benign, and per global rule the ClinVar submission must be 3★ expert panel to qualify. Neither condition is met.
clinvar
BP7 N/A Synonymous variants only; this is a missense substitution (c.428C>T, p.Thr143Ile).
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