NM_058216.3:c.493A>G (p.Met165Val) in RAD51C is a missense variant in exon 3. The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for RAD51C (version 1.0.0) does not provide criterion-level rules; assessment follows generic ACMG/AMP 2015 guidelines.1 This variant is absent from gnomAD v2.1 and gnomAD-Canada and is extremely rare in gnomAD v4.1 (overall allele frequency 0.00012%, 2/1,614,182 alleles), meeting PM2 at supporting strength.2 Multiple in silico tools predict a benign effect: REVEL score 0.046, BayesDel score -0.475, and SpliceAI max delta 0.00, meeting BP4 at supporting strength.3 ClinVar reports this variant as uncertain significance (3 clinical laboratories) and benign (1 clinical laboratory). No expert panel classification is available. No publication identified mentions this specific variant.4 No functional studies, segregation data, case-control analyses, or de novo observations were identified for this variant. The variant has not been characterized experimentally. With PM2 (supporting) and BP4 (supporting) as the only applicable criteria, the evidence is balanced but insufficient for a definitive classification; the variant remains a variant of uncertain significance.
RAD51C
Final classification
VUS
PM2BP4
RAD51C
c.493A>G
p.Met165Val
This variant
NM_058216.3:c.493A>G (p.Met165Val) in RAD51C is a missense variant in exon 3. The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for RAD51C (version 1.0.0) does not provide criterion-level rules; assessment follows generic ACMG/AMP 2015 guidelines.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
RAD51C c.493A>G
PM2 + BP4
→
VUS
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_058216.3:c.493A>G is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (overall AF = 0.00012%, 2/1,614,182 alleles; highest subpopulation AF = 0.0016% in Finnish), well below the PM2 threshold of <0.1%.
gnomAD v2.1: absent.gnomAD v4.1: AF = 0.00012% (2/1614
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no impact: REVEL score 0.046 (well below the 0.5 pathogenic threshold), BayesDel score -0.475 (negative/benign prediction), and SpliceAI max delta score 0.00 (no predicted splicing alteration).
REVEL: 0.046 (benignbelow 0.5 threshold).BayesDel: -0.475 (benign
Assessed · not applied
· 9 not met · 12 not assessed
Pathogenic
PS1
No prior pathogenic variant at the same amino acid position (Met165) identified in ClinVar or VCEP materials for comparison.
PS2
No de novo observation data with confirmed maternity/paternity available for this variant.
PS3
No well-established functional studies demonstrating a deleterious effect for NM_058216.3:c.493A>G were identified.
PS4
No case-control studies or aggregate patient data reporting NM_058216.3:c.493A>G prevalence in affected versus unaffected individuals were identified.
PM1
Residue Met165 is not located in a known mutational hotspot or well-established critical functional domain.
PM5
No pathogenic missense variant at the same residue (Met165) with a different amino acid change was identified in ClinVar for PM5 comparator analysis.
PM6
No de novo observation (with or without confirmed parentage) has been reported for NM_058216.3:c.493A>G.
PP1
No co-segregation data available for NM_058216.3:c.493A>G in affected families.
PP2
RAD51C is a moderate-penetrance cancer predisposition gene with both missense and truncating pathogenic variants.
PP3
Multiple in silico tools predict a benign effect: REVEL score 0.046 (well below 0.5 damaging threshold), BayesDel score -0.475 (negative/benign), and SpliceAI max delta = 0.00 (no splicing impact).
PP4
No patient phenotype or clinical data specific to NM_058216.3:c.493A>G carriers were identified for phenotype-specificity assessment.
PP5
This variant is not classified as pathogenic by any reputable source.
Benign
BA1
This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BA1 threshold of >1%.
BS1
This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BS1 threshold of >0.3%.
BS2
No data on observation of NM_058216.3:c.493A>G in healthy adults in the absence of disease phenotype were identified.
BS3
No well-established functional studies demonstrating no deleterious effect for NM_058216.3:c.493A>G were identified.
BS4
No segregation data available to demonstrate lack of co-segregation with disease.
BP1
RAD51C is a tumor suppressor gene in which both missense and truncating variants are established disease mechanisms; a missense change in this gene does not meet BP1, which requires that the gene cause disease primarily through truncating variants.
BP2
No data on observation of NM_058216.3:c.493A>G in trans with a known pathogenic variant were identified.
BP5
No data on observation of NM_058216.3:c.493A>G in a case where an alternative molecular basis for disease was identified.
BP6
One ClinVar submitter (Ambry Genetics) classifies this variant as benign, but this is a single submitter without expert panel review.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23902e-06; MAF= 0.00012%, 2/1614182 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56162e-05; MAF= 0.00156%, 1/64036 alleles, homozygotes = 0).
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
0.00012%
· 2 / 1,614,182
0 hom
0 hom
European (Finnish) 1 / 64,036 |
0.0016% |
European (non-Finnish) 1 / 1,180,030 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 482171)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.046. BayesDel score = -0.475232.
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. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
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
9Sources
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23188549 ↗
NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR