NM_002878.4:c.446T>A

RAD51D · NP_002869.3:p.(Leu149Gln) · NM_002878.4

GRCh37: chr17:33434041 A>T · GRCh38: chr17:35107022 A>T

Gene: RAD51D Transcript: NM_002878.4

Final call

VUS

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Leu149Gln)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002878.4:c.446T>A (p.Leu149Gln) is a missense variant in exon 5 of RAD51D, a moderate-penetrance breast and ovarian cancer susceptibility gene.

Population frequency data from gnomAD v2.1 and v4.1 are unavailable; gnomAD-Canada reports zero observations. The variant cannot be confirmed as absent or rare in population controls.

In silico predictions are inconclusive: REVEL (0.434) is intermediate, BayesDel (0.295) is borderline, and SpliceAI predicts no splicing impact (max delta 0.03). Neither PP3 nor BP4 criteria are met.

The variant is reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics/Invitae, SCV007364796) with criteria provided.

No functional studies, de novo reports, segregation data, case-control studies, or same-residue pathogenic comparators were identified for this variant.

No pathogenic or benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS) per 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	This is a missense variant (p.Leu149Gln) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant with the same amino acid change (p.Leu149Gln) has been identified in ClinVar or the literature. The ClinVar entry for this exact variant is classified as Uncertain significance.	clinvar
PS2	Not assessed	No de novo data are available for this variant. The exploratory literature search yielded no de novo reports.
PS3	Not assessed	No well-established functional studies were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
PS4	Not assessed	No case-control or cohort studies reporting prevalence of this variant in affected versus control populations were identified. The single ClinVar-associated PMID (28492532) is a methodology paper describing the Sherloc classification framework and does not report variant-specific case observations.	PMID:28492532
PS5	Not met	No reputable source reports this variant as pathogenic. The sole ClinVar submission (Labcorp Genetics/Invitae, SCV007364796) classifies this variant as Uncertain significance, not pathogenic.	clinvar
PM1	Not assessed	This variant is not located in a statistically significant mutational hotspot. Domain-level assessment of whether codon 149 lies within a critical functional domain without benign variation is not available from the evidence collected.
PM2	Not assessed	Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable (null) for this variant; gnomAD-Canada reports zero allele counts with zero total alleles. The absence of coverage data in the major gnomAD datasets precludes confident determination that the variant is truly absent from population controls.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same amino acid residue (Leu149) was identified in ClinVar. The automated PM5 candidate search yielded zero same-residue comparator variants.	clinvar
PM6	Not assessed	No de novo reports for this variant were identified. The exploratory literature search yielded no results.
PP1	Not assessed	No cosegregation data are available for this variant. No family studies or linkage analysis were identified in the literature.
PP2	Not assessed	RAD51D HCI prior data are unavailable. Without gene-level missense constraint metrics (z-score, gnomAD missense constraint), the rate of benign missense variation in RAD51D cannot be evaluated for PP2 applicability.
PP3	Not met	In silico predictions do not provide consistent evidence of a deleterious effect. REVEL score (0.434) is intermediate, below the typical pathogenic threshold of 0.75. BayesDel score (0.295) is borderline, only marginally above the ~0.27 damaging cutoff. SpliceAI predicts no splicing impact (max delta score 0.03). Multiple lines of computational evidence do not converge on a deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for review. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source reports this variant as pathogenic. The sole ClinVar submission classifies the variant as Uncertain significance.	clinvar
BA1	Not assessed	Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable. The >1% threshold cannot be evaluated without population frequency data.
BS1	Not assessed	Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable. The >0.3% threshold cannot be evaluated without population frequency data.
BS2	Not assessed	No homozygous or hemizygous observations of this variant have been reported. gnomAD homozygote data are unavailable.
BS3	Not assessed	No well-established functional studies showing no damaging effect were identified for this variant.
BS4	Not assessed	No segregation data are available to evaluate lack of segregation with disease in affected families.
BP1	Not assessed	RAD51D is a DNA repair gene where both truncating and missense variants can be pathogenic. RAD51D missense variants have been reported in association with hereditary breast and ovarian cancer. Insufficient evidence to determine that RAD51D is a gene for which primarily truncating variants cause disease.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant in RAD51D or other genes.
BP4	Not met	In silico predictions do not provide consistent evidence of no impact. REVEL score (0.434) is not in the benign range (≤0.15). BayesDel score (0.295) is not clearly below the benign threshold. While SpliceAI predicts no splicing impact (max delta 0.03), multiple lines of computational evidence do not converge on a benign prediction.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in cases harboring this variant.
BP6	Not met	No reputable source reports this variant as benign. The sole ClinVar submission classifies the variant as Uncertain significance, not benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.446T>A, p.Leu149Gln), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact.

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