NM_002878.3:c.26G>T

RAD51D · NP_002869.3:p.(Cys9Phe) · NM_002878.3

GRCh37: chr17:33446607 C>A · GRCh38: chr17:35119588 C>A

Gene: RAD51D Transcript: NM_002878.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.3

Protein

NP_002869.3:p.(Cys9Phe)

gnomAD AF

6.202235037418084e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002878.3:c.26G>T (p.Cys9Phe) is a missense variant in exon 1 of RAD51D, a gene associated with autosomal dominant hereditary breast and ovarian cancer predisposition.

This variant is extremely rare in population databases: gnomAD v2.1 reports 1 allele in 31,360 (AF=0.00319%) and gnomAD v4.1 reports 1 allele in 1,612,322 (AF=0.00006%), meeting PM2 at supporting level.

Multiple lines of computational evidence (REVEL 0.278, BayesDel 0.260, SpliceAI max delta 0.00) suggest this variant does not have a deleterious effect on protein function or splicing, meeting BP4 at supporting level.

PVS1 is not applicable as this is a missense substitution, not a null variant.

No functional studies, segregation data, de novo observations, case-control data, or pathogenic assertions from reputable sources are available for this variant.

The variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (ClinVar Variation ID: 472595), and has been observed once in somatic cancers (COSMIC COSV50100981).

The net evidence profile (PM2_supporting + BP4_supporting) results in an overall classification of Uncertain significance under ACMG/AMP 2015 combination rules.

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	NM_002878.3:c.26G>T is a missense variant (p.Cys9Phe) in exon 1 and does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense substitutions.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternate nucleotide change at position c.26 has been reported as pathogenic in ClinVar or the literature. A pathogenic comparator at the same nucleotide position is required for PS1.	clinvar
PS2	Not met	No de novo observations have been reported for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed.	clinvar
PS3	Not met	No variant-specific functional studies have been reported. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no associated functional evidence. One ClinVar submitter (Color Health) explicitly stated that functional studies have not been reported for this variant.	oncokb clinvar
PS4	Not met	No case-control studies demonstrate statistically significant enrichment of this variant in affected individuals versus controls. The variant is present in 1 of 31,360 alleles in gnomAD v2.1 and observed only once in somatic COSMIC (COSV50100981, n=1). No published cohort studies report this variant in affected individuals.	gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has recently classified this variant as pathogenic. ClinVar lists this variant as Uncertain significance across all 5 clinical laboratory submissions. No expert panel has reviewed this variant.	clinvar
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot. Hotspot analysis confirms: 'exact_variant_listed: no' and 'residue_significant: false'.
PM2	Met	This variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 31,360 (AF=0.00319%), and gnomAD v4.1 reports 1 allele in 1,612,322 (AF=0.00006%). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (Cys9) pathogenic comparator variant was identified to enable PM5 assessment. PM5 candidate harvesting was attempted but returned no eligible comparators.	pm5_candidates
PM6	Not met	No de novo observations have been reported for this variant. PM6 requires a de novo observation with confirmed maternity and paternity (without confirmation, this is downgraded to supporting level).	clinvar
PP1	Not met	No segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members.
PP2	Not assessed	Insufficient gene-level data to determine whether RAD51D has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. Pre-computed missense constraint metrics (e.g., Z-score, missense gnomAD constraint) were not available in the case data.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (well below the typical pathogenic threshold of 0.5), BayesDel score is 0.260 (low positive), and SpliceAI predicts no splicing impact (max delta score = 0.00). The weight of computational evidence argues against pathogenicity.	revel bayesdel spliceai
PP4	Not met	No specific phenotype or family history data are available for individuals carrying this variant. PP4 requires that the variant has been observed in multiple unrelated patients with a phenotype highly specific for the gene/disease.	clinvar
PP5	Not met	No reputable source has classified this variant as pathogenic. All 5 ClinVar clinical laboratory submissions classify this variant as Uncertain significance. The publications cited by submitters (PMID:25741868, PMID:28492532) are general classification methodology papers and do not assert pathogenicity for this specific variant.	clinvar
BA1	Not met	The maximum allele frequency observed in any population is 0.00649% (gnomAD v2.1, European non-Finnish). This is far below the 1% threshold for BA1. The variant is not common in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency observed is 0.00649% (gnomAD v2.1 NFE), well below the 0.3% threshold for BS1. The variant is extremely rare rather than common in the general population.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in a homozygous state in gnomAD (0 homozygotes in both v2.1 and v4.1), and no data exist demonstrating observation in healthy adult controls without disease. BS2 criteria are not satisfied.	gnomad_v2 gnomad_v4
BS3	Not met	No variant-specific functional studies demonstrating a neutral or benign effect have been reported. OncoKB shows no functional evidence for this variant and classifies its effect as unknown.	oncokb
BS4	Not met	No evidence is available demonstrating lack of segregation with disease in affected families. BS4 requires non-segregation data.
BP1	Not met	RAD51D is a gene in which both missense and truncating variants can be pathogenic. BP1 applies to missense variants in genes where only truncating variants are a known disease mechanism, which is not the case for RAD51D.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic RAD51D variant has been reported for a fully penetrant dominant disorder. BP2 requires co-occurrence in trans with a pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest this variant does not impact protein function or splicing. REVEL score of 0.278 is well below the pathogenic threshold of 0.5. BayesDel score of 0.260 is weakly positive. SpliceAI predicts no splicing impact (max delta = 0.00). The weight of in silico evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in individuals carrying this variant. BP5 requires observation in a case with an alternate molecular cause, which has not been reported.
BP6	Not met	No reputable source classifies this variant as benign. All 5 ClinVar submissions classify the variant as Uncertain significance. BP6 requires a reputable source to have classified the variant as benign.	clinvar
BP7	N/A	BP7 applies exclusively to synonymous (silent) variants. NM_002878.3:c.26G>T is a missense variant (p.Cys9Phe) and is not eligible for BP7 assessment.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a substitution.
PM3	N/A	PM3 is for recessive disorders with a pathogenic variant in trans. RAD51D-associated cancer predisposition is an autosomal dominant condition.
PM4	N/A	PM4 applies to in-frame insertions/deletions 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.