PM1_Supporting: The variant alters Gly153, located within the Walker A motif (GAPGVGKT) of the RAD51C ATPase domain, a critical functional domain where pathogenic missense variants cluster and benign variation is absent in population databases.1 PM2_Supporting: The variant is extremely rare in population databases (gnomAD v2.1 AF=7.95e-06, 2/251,462 alleles; gnomAD v4.1 AF=1.86e-06, 3/1,614,194 alleles; both well below the PM2 threshold of <0.1%).2 PP3_Supporting: Multiple computational tools predict a deleterious effect. REVEL score is 0.635. Both SIFT and PolyPhen predicted G153D as likely pathogenic based on sequence conservation (PMID:21980511).3 PS3 not assessed: Functional studies (PMID:37253112, PMID:36099300, PMID:39299233) describe deleterious effects for variants in the Walker A/ATP-binding region where Gly153 resides, but the abstracts do not confirm that p.Gly153Asp was among the specific variants tested and shown to be functionally deleterious. Full-text review of these papers is required to determine PS3 applicability.4 The variant was identified in germline DNA of BRCA-negative breast and/or ovarian cancer cases in Clague et al. (PMID:21980511), which screened 286 high-risk families and found G153D among six non-synonymous variants. No truncating mutations were identified in this cohort.5 In ClinVar (Variation ID 185444), the majority classification is Uncertain significance (7 clinical laboratories), while three laboratories classify as Likely pathogenic and one as Pathogenic (LOVD, no criteria provided). No ClinGen expert panel review is available.6 Overall assessment: 3 supporting pathogenic criteria met (PM1_Supporting, PM2_Supporting, PP3_Supporting). Per ACMG/AMP 2015 combination rules, a minimum of 2 moderate or 1 moderate + 2 supporting criteria is needed for Likely pathogenic. With only 3 supporting criteria, the classification remains Variant of Uncertain Significance. PS3 assessment (pending full-text review of functional studies) could potentially elevate the classification to Likely pathogenic if moderate-level functional evidence is confirmed.7
RAD51C
Final classification
VUS
RAD51C c.458G>A · p.Gly153Asp
RAD51C
PM1_Supporting: The variant alters Gly153, located within the Walker A motif (GAPGVGKT) of the RAD51C ATPase domain, a critical functional domain where pathogenic missense variants cluster and benign variation is absent in population databases.
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: PM1 supporting, PM2 supporting, PP3 supporting; combination = 3 supporting, which maps to VUS.
Classification rationale
PM1PM2PP3
VUS
RAD51C c.458G>A
PM1 + PM2 + PP3
→
VUS
3
revelPMID:21980511 ↗
7
generic_acmg_combination_rules
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85851e-06; MAF= 0.00019%, 3/1614194 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66622e-05; MAF= 0.00167%, 1/60016 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95349e-06; MAF= 0.00080%, 2/251462 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,194
0 hom
0 hom
Admixed American 1 / 60,016 |
0.0017% |
Remaining individuals 1 / 62,510 |
0.0016% |
European (non-Finnish) 1 / 1,180,028 |
8.5e-05% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 251,462
0 hom
0 hom
Admixed American 1 / 34,592 |
0.0029% |
European (non-Finnish) 1 / 113,750 |
0.00088% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 185444)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.635. BayesDel score = 0.233494.
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.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.
RAD51C germline mutations in breast and ovarian cancer cases from high-risk families.
Found
SIFT and PolyPhen both predicted G153D as likely pathogenic.
Applied to
→PP3 supports · met
Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants.
Found
identifies a cluster of HR-deficient mutations in and around the Walker A box.
Applied to
→PM1 supports · met
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.
Found
identifies 18 nonfunctional variants in a hotspot within the ATP-binding region.
Applied to
→PM1 supports · met
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR