LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-04
Case ID: NM_058216.3_c.848C_T_20260704_201022
Framework: ACMG/AMP 2015
Variant classification summary

NM_058216.3:c.848C>T

RAD51C  · NP_478123.1:p.(Thr283Ile)  · NM_058216.3
GRCh37: chr17:56798117 C>T  ·  GRCh38: chr17:58720756 C>T
Gene: RAD51C Transcript: NM_058216.3
Final call
VUS
PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD51C
Transcript
NM_058216.3
Protein
NP_478123.1:p.(Thr283Ile)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The variant NM_058216.3:c.848C>T (p.Thr283Ile) in RAD51C is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting strength.
2
The variant is a missense change not triggering PVS1. No alternative pathogenic missense at the same residue (PM5), no de novo observations (PS2/PM6), no functional studies (PS3/BS3), no case-control or prevalence data (PS4), no segregation data (PP1/BS4), and no patient phenotype data (PP4) are available.
3
In silico predictors are mixed: REVEL (0.308) is indeterminate, BayesDel (0.074) is in the benign range, and SpliceAI predicts no splice impact (0.00). Neither PP3 nor BP4 is met.
4
The RAD51C Hereditary Breast, Ovarian and Pancreatic Cancer VCEP specification (v1.0.0, doc_id 1535377178) is in preparation and does not provide finalized criterion-specific rules. Assessment defaults to generic ACMG/AMP 2015 guidelines (PMID:25741868).
5
Under generic ACMG/AMP 2015 combination rules, a single supporting pathogenic criterion (PM2) is insufficient to reach Likely Pathogenic. No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).
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 NM_058216.3:c.848C>T is a missense variant (p.Thr283Ile) and does not fall into the null-variant buckets of nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon-level deletion that trigger PVS1 under the ClinGen SVI PVS1 framework (PMC6185798).
pvs1_variant_assessment pvs1_generic_framework
PS1 Not met No alternative nucleotide change at codon 848 producing the same p.Thr283Ile amino acid substitution has been reported as pathogenic. The variant is absent from ClinVar, and no pathogenic comparator at this residue exists in available databases.
clinvar
PS2 Not met No de novo observation with confirmed maternity and paternity has been reported for this variant in any available source.
PS3 Not met No well-established in vitro or in vivo functional studies assessing the impact of p.Thr283Ile on RAD51C protein function were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.
oncokb
PS4 Not met No case-control studies or prevalence comparisons between affected individuals and controls are available. The variant has not been reported in any affected individual in ClinVar, COSMIC, or the literature.
clinvar
PS5 Not met No evidence that this variant has been found in a case with an alternate molecular basis for disease. No case-level data are available.
PM1 Not met The p.Thr283Ile substitution does not lie within a statistically significant mutational hotspot in RAD51C, and no VCEP-defined critical functional domain assignment is available for this residue.
PM2 Met The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines.
gnomad_v2 gnomad_v4 gnomad_canada
PM5 Not met No pathogenic missense variant at the same amino acid residue (Thr283) with a different amino acid change has been identified. The PM5 candidate search returned no comparator variants at this residue.
pm5_candidates clinvar
PM6 Not met No de novo observation (with or without confirmed maternity and paternity) has been reported for this variant. PM6 requires at least a de novo observation without parental confirmation.
PP1 Not met No cosegregation data are available. No family studies or pedigrees including this variant have been reported.
PP2 Not met RAD51C is not included in the HCI prior gene set, so a gene-level missense constraint metric cannot be calculated. Without evidence that RAD51C has a low rate of benign missense variation and that missense variants are a common pathogenic mechanism, PP2 cannot be applied.
PP3 Not met In silico predictors do not support a deleterious effect. REVEL score is 0.308 (below the 0.5 threshold for pathogenicity), BayesDel score is 0.074 (within the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00).
revel bayesdel spliceai
PP4 Not met No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for RAD51C-associated disease (hereditary breast/ovarian cancer, Fanconi anemia).
PP5 Not met No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as pathogenic with unavailable supporting evidence.
clinvar
BA1 Not met The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, far below the BA1 threshold of >1% (or >0.1% for recessive Fanconi anemia context).
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met The variant is absent from population databases. The observed allele frequency (0%) is not greater than expected for the disorder; BS1 requires an allele frequency higher than expected for the disease prevalence.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met The variant has not been observed in any individual (healthy or affected) in available databases. No healthy adult observation data exist to apply BS2.
BS3 Not met No well-established in vitro or in vivo functional studies demonstrating no damaging effect of this variant on RAD51C protein function or splicing are available.
BS4 Not met No segregation data are available to assess lack of cosegregation with disease. BS4 requires evidence that the variant does not segregate with disease in affected family members.
BP1 N/A RAD51C is known to harbor pathogenic missense variants (e.g., homozygous missense reported in Fanconi anemia-like disorder, PMID:20400963). BP1 is only applicable to genes where truncating variants are the sole disease mechanism.
pvs1_gene_context
BP2 Not met No observation of this variant in trans with a known pathogenic RAD51C variant has been reported for a fully penetrant dominant disorder.
BP4 Not met Computational predictors yield mixed results: BayesDel (0.074) is in the benign range and SpliceAI (0.00) predicts no splice impact, but REVEL (0.308) is indeterminate and does not clearly support a benign effect. Multiple lines of evidence do not converge on a benign prediction.
revel bayesdel spliceai
BP5 Not met No case has been reported in which this variant is found in an individual with an alternate molecular basis for disease. No case-level data are available.
BP6 Not met No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as benign or likely benign.
clinvar
BP7 N/A NM_058216.3:c.848C>T is a missense variant (p.Thr283Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.
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