NM_058216.3:c.493A>G

RAD51C · NP_478123.1:p.(Met165Val) · NM_058216.3

GRCh37: chr17:56774142 A>G · GRCh38: chr17:58696781 A>G

Gene: RAD51C Transcript: NM_058216.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.(Met165Val)

gnomAD AF

1.2390176572406333e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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.

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	Not a null variant; missense substitution NM_058216.3:c.493A>G (p.Met165Val) does not fall into PVS1 buckets (nonsense, frameshift, or canonical splice consensus).
PS1	Not assessed	No prior pathogenic variant at the same amino acid position (Met165) identified in ClinVar or VCEP materials for comparison.
PS2	Not assessed	No de novo observation data with confirmed maternity/paternity available for this variant.
PS3	Not met	No well-established functional studies demonstrating a deleterious effect for NM_058216.3:c.493A>G were identified. OncoKB reports no variant-specific functional evidence. No publication mentions this variant.	oncokb
PS4	Not assessed	No case-control studies or aggregate patient data reporting NM_058216.3:c.493A>G prevalence in affected versus unaffected individuals were identified.
PS5	Not met	ClinVar reports uncertain significance (3 clinical laboratories) and benign (1 laboratory); no reputable source classifies this variant as pathogenic.	clinvar
PM1	Not met	Residue Met165 is not located in a known mutational hotspot or well-established critical functional domain. Hotspot analysis confirmed no statistically significant enrichment at this position.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same residue (Met165) with a different amino acid change was identified in ClinVar for PM5 comparator analysis.
PM6	Not assessed	No de novo observation (with or without confirmed parentage) has been reported for NM_058216.3:c.493A>G.
PP1	Not assessed	No co-segregation data available for NM_058216.3:c.493A>G in affected families.
PP2	Not assessed	RAD51C is a moderate-penetrance cancer predisposition gene with both missense and truncating pathogenic variants. No VCEP-specific PP2 rule is available, and insufficient data exist to determine whether RAD51C has a low rate of benign missense variation to meet generic PP2.
PP3	Not met	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). These findings support a benign interpretation rather than PP3.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data specific to NM_058216.3:c.493A>G carriers were identified for phenotype-specificity assessment.
PP5	Not met	This variant is not classified as pathogenic by any reputable source. ClinVar reports uncertain significance (3 submitters) and benign (1 submitter). No expert panel classification is available.	clinvar
BA1	Not met	This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	This variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00012%), far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not assessed	No data on observation of NM_058216.3:c.493A>G in healthy adults in the absence of disease phenotype were identified.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect for NM_058216.3:c.493A>G were identified.
BS4	Not assessed	No segregation data available to demonstrate lack of co-segregation with disease.
BP1	Not met	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	Not assessed	No data on observation of NM_058216.3:c.493A>G in trans with a known pathogenic variant were identified.
BP3	N/A	In-frame deletions/insertions in non-repeat regions are not applicable to this substitution variant.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No data on observation of NM_058216.3:c.493A>G in a case where an alternative molecular basis for disease was identified.
BP6	Not met	One ClinVar submitter (Ambry Genetics) classifies this variant as benign, but this is a single submitter without expert panel review. Generic BP6 requires a reputable source classification; a single clinical laboratory report does not meet this threshold.	clinvar
BP7	N/A	NM_058216.3:c.493A>G is a missense variant (p.Met165Val), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact.

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