Classification rationale

PM2 BP4 VUS

RAD51C c.187A>T

PM2 (Supporting): absent from gnomAD v2.1 and v4.1 (~856k exomes combined), allele frequency 0. BP4 (Supporting): REVEL 0.084 falls in the SVI-calibrated benign-leaning interval (0.016-0.183). VUS: PM2 (pathogenic direction) and BP4 (benign direction) conflict at supporting strength, satisfying no ACMG/AMP combination rule.

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 · 22 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1 (~125.7k exomes) and v4.1 (~730.9k exomes), allele frequency 0.

gnomAD v2.1 (exome, ~125.7k individuals): variant 17-56772333-A-T absent (search_status 'absent', found=false, AF=0) (registry key: gnomad_v2).gnomAD v4.1 (exome, ~730.9k individuals): variant chr17-58694972-A-T absent (search_status 'absent', found=false, AF=0) (registry key: gnomad_v4).Generic ACMG/AMP 2015 PM2: absent in large population cohorts (or extremely low frequency if recessive) (Richards et al. 2015, PMID 25741868); local non-VCEP operating threshold PM2 <0.1% (registry key: generic_acmg_combination_rules). Absence (AF=0) satisfies PM2.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.084 falls in the SVI-calibrated BP4 interval (0.016-0.183), strongly benign-leaning.

REVEL score 0.084 falls within the ClinGen SVI-calibrated REVEL BP4 moderate interval (0.016 < score <= 0.183; Pejaver et al. 2022, Am J Hum Genet, PMID 36413997, Table 2); BP4 applied at supporting strength per the governing generic ACMG/AMP fallback framework (Richards et al. 2015, PMID 25741868), which caps PP3/BP4 at supporting.BayesDel noAF score -0.3387 falls within the SVI-calibrated BayesDel BP4 supporting interval (-0.36 < score <= -0.18; Pejaver et al. 2022, PMID 36413997, Table 2); concordant with BP4 but not counted as a separate line (single-tool framework for missense).SpliceAI max delta 0.01, below the 0.2 splice-altering threshold (Jaganathan et al. 2019, Cell, PMID 30661751); concordant with no splice impact, but the splice path does not independently govern for a missense variant; not counted as a separate line.

spliceai ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 Not met: no established pathogenic variant producing the same amino acid change p.(Ile63Phe) is documented.

PS2 Not assessed: no proband or parental genotype data were available to evaluate a de novo occurrence.

PS3 Not assessed: no functional assay evidence for p.(Ile63Phe) was identified in any consulted source.

PS4 Not assessed: no case-control or case-series data exist for this exact variant.

PM1 Not met: residue 63 is not a documented cancer hotspot, and no functional-domain annotation was available.

PM3 Not assessed: no biallelic or in-trans observation of c.187A>T with a pathogenic RAD51C variant is documented.

PM5 Not met: no pathogenic missense variant at a different amino acid at residue 63 is documented.

PM6 Not assessed: no de novo occurrence is reported and no proband or parental genotype data exist.

PP1 Not assessed: no segregation data exist for c.187A>T - no affected family members were genotyped.

PP2 Not met: missense is not a common mechanism of RAD51C disease, which is predominantly loss-of-function.

PP3 Not met: REVEL 0.084 is far below the >=0.644 threshold for a damaging prediction.

PP4 Not assessed: no proband phenotype or family-history information is available for any carrier.

PP5 Not met: no ClinVar expert-panel pathogenic classification exists; only a single-laboratory Benign assertion.

Benign

BA1 Not met: allele frequency is 0 (absent from gnomAD), far below the >1% BA1 threshold.

BS1 Not met: allele frequency is 0, far below the >0.3% BS1 threshold.

BS2 Not met: no healthy-adult or control observation exists; zero carriers among ~856k gnomAD exomes.

BS3 Not assessed: no well-established functional study of p.(Ile63Phe) is available.

BS4 Not assessed: no affected family members were genotyped, so non-segregation cannot be evaluated.

BP1 Not met: missense variants are an established disease mechanism in RAD51C, so BP1's truncating-only precondition fails.

BP2 Not assessed: no cis/trans phase observation relative to a pathogenic RAD51C variant exists.

BP5 Not assessed: no case data exist to evaluate an alternative molecular cause of disease.

BP6 Not met: the Benign label is from a single laboratory, not a ClinVar expert panel, so BP6's precondition fails.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1781854)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.084. BayesDel score = -0.338738.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Rule & framework references · cited for criterion definitions, not variant evidence

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots