NM_133509.4:c.121G>A

RAD51B · NP_598193.2:p.(Val41Met) · NM_133509.4

GRCh37: chr14:68292217 G>A · GRCh38: chr14:67825500 G>A

Gene: RAD51B Transcript: NM_133509.4

Final call

Likely Benign

PM2 supporting BP1 supporting BP4 supporting

Variant details

Gene

RAD51B

Transcript

NM_133509.4

Protein

NP_598193.2:p.(Val41Met)

gnomAD AF

6.197276668740688e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_133509.4:c.121G>A (p.Val41Met) is a missense variant in RAD51B, a gene in which loss-of-function truncating variants are the established germline disease mechanism for melanoma and breast/ovarian cancer predisposition.

This variant is extremely rare in population databases: present at an allele frequency of 6.20e-07 in gnomAD v4.1 (1/1,613,612 alleles) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting strength.

Multiple in silico predictors are concordant for a benign effect: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no splice impact), meeting BP4 at supporting strength.

As a missense variant in a gene where truncating variants are the primary pathogenic mechanism, BP1 applies at supporting strength.

The variant is absent from ClinVar; no functional studies, segregation data, case-control data, or de novo observations are available. No publications specifically mention NM_133509.4:c.121G>A.

With one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4), the net evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS).

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	Missense variant (p.Val41Met); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 generic framework not applicable.	pvs1_variant_assessment
PS1	Not met	No pathogenic missense variant at the same amino acid position has been established in ClinVar or the literature to support PS1.	clinvar
PS2	Not assessed	No de novo data are available for this variant.
PS3	Not met	No functional studies have been reported for NM_133509.4:c.121G>A (p.Val41Met). OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence.	oncokb
PS4	Not assessed	No case-control or enrichment data are available for this variant.
PS5	Not assessed	No data are available regarding observation in trans with a pathogenic variant for a recessive disorder.
PM1	Not met	Residue 41 does not lie within a statistically significant mutational hotspot (cancerhotspots.org). No variant-specific domain-level functional characterization has been identified for this position.
PM2	Met	Extremely low population frequency: gnomAD v4.1 AF = 6.20e-07 (1/1,613,612 alleles, no homozygotes). Absent from gnomAD v2.1 and gnomAD-Canada. Well below the 0.1% PM2 threshold for rare diseases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variants identified in ClinVar; automatic PM5 candidate harvesting was unsuccessful.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant.
PP1	Not assessed	No co-segregation data are available for this variant.
PP2	Not assessed	No gene-level constraint data (e.g., missense Z-score, o/e ratio) are available to assess whether RAD51B has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors support a benign impact: REVEL score 0.039 (well below pathogenic threshold of ~0.5), BayesDel score -0.491 (negative, predicting benign), SpliceAI max delta 0.13 (no significant splice impact).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess disease specificity.
PP5	Not met	Absent from ClinVar; no reputable source has reported NM_133509.4:c.121G>A as pathogenic.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 6.20e-07, far below the 1% BA1 threshold for standing benign variation.	gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 6.20e-07, far below the 0.3% BS1 threshold for benign standing variation in rare disease genes.	gnomad_v4
BS2	Not assessed	No data are available regarding observation in healthy adults independent of disease status.
BS3	Not met	No experimental functional studies demonstrating a neutral effect have been reported for this variant. In silico predictions alone do not satisfy BS3, which requires direct functional evidence.
BS4	Not assessed	No segregation data are available to assess lack of segregation with disease.
BP1	Met	Missense variant (p.Val41Met) in RAD51B, a gene in which loss-of-function truncating variants are the established germline disease mechanism. Published germline RAD51B mutations associated with melanoma and breast/ovarian cancer predisposition are predominantly truncating or splice-disrupting.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation in trans with a pathogenic dominant variant.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no significant splice impact). All in silico predictors are concordant for a benign effect.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular basis for disease has been identified in this case.
BP6	Not met	Absent from ClinVar; no reputable source has reported NM_133509.4:c.121G>A as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (c.121G>A, p.Val41Met).

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.