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.1 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.2 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.3 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).4 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).5
RAD51C
Final classification
VUS
PM2
RAD51C
c.848C>T
p.Thr283Ile
This variant
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.
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; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
RAD51C c.848C>T
PM2
→
VUS
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 1 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes)absent from gnomAD v4.1 (exomes)absent from gnomAD-Canada v1.0 (genomes).
Assessed · not applied
· 21 not met · 0 not assessed
Pathogenic
PS1
No alternative nucleotide change at codon 848 producing the same p.Thr283Ile amino acid substitution has been reported as pathogenic.
PS2
No de novo observation with confirmed maternity and paternity has been reported for this variant in any available source.
PS3
No well-established in vitro or in vivo functional studies assessing the impact of p.Thr283Ile on RAD51C protein function were identified.
PS4
No case-control studies or prevalence comparisons between affected individuals and controls are available.
PM1
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.
PM5
No pathogenic missense variant at the same amino acid residue (Thr283) with a different amino acid change has been identified.
PM6
No de novo observation (with or without confirmed maternity and paternity) has been reported for this variant.
PP1
No cosegregation data are available.
PP2
RAD51C is not included in the HCI prior gene set, so a gene-level missense constraint metric cannot be calculated.
PP3
In silico predictors do not support a deleterious effect.
PP4
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
No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as pathogenic with unavailable supporting evidence.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from population databases.
BS2
The variant has not been observed in any individual (healthy or affected) in available databases.
BS3
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
No segregation data are available to assess lack of cosegregation with disease.
BP2
No observation of this variant in trans with a known pathogenic RAD51C variant has been reported for a fully penetrant dominant disorder.
BP4
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.
BP5
No case has been reported in which this variant is found in an individual with an alternate molecular basis for disease.
BP6
No reputable source (clinical laboratory, curated database, or expert panel) has reported this variant as benign or likely benign.
N/A · 3
PVS1 · BP1 · 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
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.308. BayesDel score = 0.0741864.
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