NM_058216.3:c.187A>T

RAD51C · NP_478123.1:p.(Ile63Phe) · NM_058216.3

GRCh37: chr17:56772333 A>T · GRCh38: chr17:58694972 A>T

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.(Ile63Phe)

gnomAD AF

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback: the combination of 1 supporting pathogenic-direction criterion (PM2) plus 1 supporting benign-direction criterion (BP4) meets no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule; all other combinations, including conflicting pathogenic and benign evidence, are 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 applicable: c.187A>T is a missense change, and PVS1 applies only to null variants such as nonsense or frameshift.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant producing the same amino acid change p.(Ile63Phe) is documented.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband or parental genotype data were available to evaluate a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay evidence for p.(Ile63Phe) was identified in any consulted source.	oncokb spliceai clinvar PMID:25394175
PS4	Not assessed	Not assessed: no case-control or case-series data exist for this exact variant.	clinvar PMID:25394175
PM1	Not met	Not met: residue 63 is not a documented cancer hotspot, and no functional-domain annotation was available.	cspec pvs1_variant_assessment
PM2	Met	Met (supporting): absent from gnomAD v2.1 (~125.7k exomes) and v4.1 (~730.9k exomes), allele frequency 0.	cspec gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no biallelic or in-trans observation of c.187A>T with a pathogenic RAD51C variant is documented.	cspec clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25394175
PM4	N/A	Not applicable: PM4 concerns protein-length changes; c.187A>T is a missense substitution that preserves length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no pathogenic missense variant at a different amino acid at residue 63 is documented.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no de novo occurrence is reported and no proband or parental genotype data exist.
PP1	Not assessed	Not assessed: no segregation data exist for c.187A>T - no affected family members were genotyped.
PP2	Not met	Not met: missense is not a common mechanism of RAD51C disease, which is predominantly loss-of-function.	pvs1_gene_context generic_acmg_combination_rules
PP3	Not met	Not met: REVEL 0.084 is far below the >=0.644 threshold for a damaging prediction.	revel bayesdel spliceai cspec generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history information is available for any carrier.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel pathogenic classification exists; only a single-laboratory Benign assertion.	clinvar
BA1	Not met	Not met: allele frequency is 0 (absent from gnomAD), far below the >1% BA1 threshold.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0, far below the >0.3% BS1 threshold.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: no healthy-adult or control observation exists; zero carriers among ~856k gnomAD exomes.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established functional study of p.(Ile63Phe) is available.	oncokb spliceai clinvar PMID:25394175
BS4	Not assessed	Not assessed: no affected family members were genotyped, so non-segregation cannot be evaluated.
BP1	Not met	Not met: missense variants are an established disease mechanism in RAD51C, so BP1's truncating-only precondition fails.	pvs1_gene_context generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase observation relative to a pathogenic RAD51C variant exists.	cspec clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25394175
BP3	N/A	Not applicable: BP3 applies to in-frame insertions/deletions in repeats; c.187A>T is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.084 falls in the SVI-calibrated BP4 interval (0.016-0.183), strongly benign-leaning.	revel bayesdel spliceai cspec generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no case data exist to evaluate an alternative molecular cause of disease.	clinvar
BP6	Not met	Not met: the Benign label is from a single laboratory, not a ClinVar expert panel, so BP6's precondition fails.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; c.187A>T is a missense substitution altering the protein.	generic_acmg_combination_rules

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