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.1 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.2 The variant is reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics/Invitae, SCV007364796) with criteria provided.3 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.4
RAD51D
Final classification
VUS
RAD51D c.446T>A · p.Leu149Gln
RAD51D
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
Classification rationale
VUS
RAD51D c.446T>A
Gene diagram
· NM_002878.4 · variants mapped to exon structure
RAD51D
NM_002878.4
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 23 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PS1
No pathogenic or likely pathogenic variant with the same amino acid change (p.Leu149Gln) has been identified in ClinVar or the literature.
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies were identified for this variant.
PS4
No case-control or cohort studies reporting prevalence of this variant in affected versus control populations were identified.
PM1
This variant is not located in a statistically significant mutational hotspot.
PM2
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.
PM5
No pathogenic or likely pathogenic missense variant at the same amino acid residue (Leu149) was identified in ClinVar.
PM6
No de novo reports for this variant were identified.
PP1
No cosegregation data are available for this variant.
PP2
RAD51D HCI prior data are unavailable.
PP3
In silico predictions do not provide consistent evidence of a deleterious effect.
PP4
No patient phenotype or family history data are available for review.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable.
BS1
Population allele frequency data from gnomAD v2.1 and v4.1 are unavailable.
BS2
No homozygous or hemizygous observations of this variant have been reported.
BS3
No well-established functional studies showing no damaging effect were identified for this variant.
BS4
No segregation data are available to evaluate lack of segregation with disease in affected families.
BP1
RAD51D is a DNA repair gene where both truncating and missense variants can be pathogenic.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant in RAD51D or other genes.
BP4
In silico predictions do not provide consistent evidence of no impact.
BP5
No data are available regarding an alternate molecular basis for disease in cases harboring this variant.
BP6
No reputable source reports this variant as benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4705017)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.434. BayesDel score = 0.294753.
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. RAD51D, a DNA repair protein, is infrequently altered in cancer.
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.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR