Classification rationale

PM2 BP4 VUS

RAD51B c.263C>G

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).¹ 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).² 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.³ 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.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_133509.4 · variants mapped to exon structure

RAD51B NM_133509.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

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%.

Absent from gnomAD v2.1 (exomes)gnomAD v4.1 (exomes)and gnomAD-Canada v1.0 (genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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 max delta: 0.02 (no splicing impact)REVEL: 0.055 (benign)BayesDel: -0.479 (benign)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No previously established pathogenic variant has been reported at amino acid position Ser88 in RAD51B.

PS2 No de novo observation has been reported for this variant in any available source.

PS3 No functional studies have been performed on NM_133509.4:c.263C>G (p.Ser88Cys) or on a systematically characterized range encompassing codon 88.

PS4 No case-control or cohort enrichment data are available for this variant.

PM1 Residue Ser88 does not lie within a statistically significant mutational hotspot in RAD51B (cancerhotspots.org).

PM5 No different pathogenic missense variant has been established at codon 88 (Ser88) of RAD51B.

PM6 No de novo observation of this variant has been reported in any available source.

PP1 No segregation data are available for this variant.

PP2 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.

PP3 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).

PP4 No patient phenotype or clinical history is available for this variant.

PP5 NM_133509.4:c.263C>G is absent from ClinVar.

Benign

BA1 The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BA1 threshold of >1% population allele frequency.

BS1 The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BS1 threshold of >0.3% population allele frequency.

BS2 No evidence of this variant observed in a homozygous state, in trans with a pathogenic variant, or in healthy adult individuals is available.

BS3 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.

BS4 No segregation data are available to demonstrate lack of cosegregation with disease.

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease.

BP2 No evidence of this variant observed in trans with a known pathogenic variant in RAD51B or in cis with a pathogenic variant is available.

BP5 No evidence is available of this variant being identified in a case with an alternate molecular basis for disease.

BP6 NM_133509.4:c.263C>G is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.055. BayesDel score = -0.479357.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51B, a DNA repair protein involved in homologous recombination, is altered by mutation in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots