NM_133509.4:c.263C>G

RAD51B · NP_598193.2:p.(Ser88Cys) · NM_133509.4

GRCh37: chr14:68301861 C>G · GRCh38: chr14:67835144 C>G

Gene: RAD51B Transcript: NM_133509.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Ser88Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_133509.4:c.263C>G (p.Ser88Cys) in RAD51B is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).

Multiple lines of in silico evidence — including REVEL (0.055), BayesDel (-0.479), and SpliceAI (max delta 0.02) — unanimously predict no damaging effect on the gene product (BP4).

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

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 guidelines.

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	PVS1 is not applicable to missense variants. This variant is a substitution producing NP_598193.2:p.(Ser88Cys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants defined by the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant has been reported at amino acid position Ser88 in RAD51B. PS1 requires a known pathogenic variant with the same amino acid change arising from a different nucleotide substitution.	clinvar pm5_candidates
PS2	Not met	No de novo observation has been reported for this variant in any available source. PS2 requires confirmation of a de novo occurrence with confirmed maternity and paternity.
PS3	Not met	No functional studies have been performed on NM_133509.4:c.263C>G (p.Ser88Cys) or on a systematically characterized range encompassing codon 88. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. In silico predictions indicate no damaging effect (REVEL 0.055, BayesDel -0.479).	oncokb revel bayesdel
PS4	Not met	No case-control or cohort enrichment data are available for this variant. The variant is absent from gnomAD, limiting statistical comparisons, and absent from ClinVar, precluding any prevalence assessment in affected individuals.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No alternative nucleotide change at codon 88 yielding the same missense change (p.Ser88Cys or another pathogenic change at this codon) has been reported as pathogenic. The PM5 candidate search identified no comparator variants at this residue.	pm5_candidates clinvar
PM1	Not met	Residue Ser88 does not lie within a statistically significant mutational hotspot in RAD51B (cancerhotspots.org). No domain-level evidence in the reviewed materials characterizes this region as a critical functional domain where missense variation is established as pathogenic. The N-terminal region of RAD51B preceding the Walker A motif (which begins around residue 106) has not been identified as a well-characterized functional domain for PM1 application.
PM2	Met	NM_133509.4:c.263C>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2 under generic ACMG/AMP rules for a variant with population allele frequency below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant has been established at codon 88 (Ser88) of RAD51B. The automated PM5 candidate search identified zero same-residue comparator variants with expert panel or majority pathogenic classifications in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo observation of this variant has been reported in any available source. PM6 requires a de novo occurrence without confirmation of paternity and maternity.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	Not met	RAD51B is not represented in the HCI prior set, and no gene-specific data are available to establish that missense variants are a common mechanism of disease with a low rate of benign missense variation in this gene. The available PVS1 gene context literature supports truncating mutations in RAD51B-associated disease, but does not establish the PP2 premise for missense variants.	pvs1_gene_context
PP3	Not met	Multiple in silico tools unanimously predict a benign or no impact: REVEL score 0.055 (well below pathogenic threshold of 0.5), BayesDel score -0.479 (negative, benign), and SpliceAI max delta score 0.02 (no predicted splicing effect). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical history is available for this variant. PP4 requires that the variant was identified in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	NM_133509.4:c.263C>G is absent from ClinVar. There is no reputable source recently classifying this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BA1 threshold of >1% population allele frequency. BA1 requires a high allele frequency incompatible with disease causation.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BS1 threshold of >0.3% population allele frequency. BS1 requires an allele frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of this variant observed in a homozygous state, in trans with a pathogenic variant, or in healthy adult individuals is available. BS2 requires observation in such contexts without disease manifestations.
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed on this variant demonstrating no damaging effect on protein function or splicing. While in silico predictions are benign-leaning (REVEL 0.055, BayesDel -0.479), in silico data alone do not satisfy BS3, which requires experimental functional evidence.	revel bayesdel
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation of non-segregation in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease. While the PVS1 gene context literature supports RAD51B truncating mutations in melanoma and breast cancer predisposition, genome-wide association studies have also identified RAD51B missense and intronic variants associated with cancer risk, and the gene is not established as exclusively truncating-mediated. The available evidence does not support that only truncating variants cause RAD51B-associated disease.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant in RAD51B or in cis with a pathogenic variant is available. BP2 requires such observations in the context of appropriate inheritance patterns.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing effect (max delta score 0.02), REVEL score of 0.055 is strongly benign-predicting, and BayesDel score of -0.479 is in the benign range. The convergence of independent in silico tools supports a lack of functional consequence for this missense change.	spliceai revel bayesdel
BP5	Not met	No evidence is available of this variant being identified in a case with an alternate molecular basis for disease. BP5 requires a documented alternative genetic cause explaining the phenotype in a case where this variant was also found.
BP6	Not met	NM_133509.4:c.263C>G is absent from ClinVar. No reputable source classifies this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This variant is a missense substitution, NM_133509.4:c.263C>G (p.Ser88Cys), and is not eligible for BP7.
BP3	N/A	BP3 applies to in-frame deletions and insertions in repetitive regions. This variant is a single-nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. RAD51B-associated cancer predisposition is not a recessive disorder.
PM4	N/A	PM4 applies to protein-length-changing variants from in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.