NM_005732.3:c.2033_2034dup is a frameshift 2bp duplication in exon 13 of RAD50, predicted to cause premature termination at codon 720 (p.Cys680HisfsTer41). RAD50 loss of function is an established mechanism for NBS-like disorder.1 This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with an allele frequency of 2.48e-6 (4/1,614,058 alleles, no homozygotes) in gnomAD v4.1, well below the PM2 threshold of 0.1%.2 This variant has been classified as Pathogenic in ClinVar by two clinical laboratories (Ambry Genetics, Labcorp Genetics).3 No variant-specific functional studies (PS3/BS3), de novo data (PS2/PM6), segregation data (PP1/BS4), or case-control enrichment data (PS4) were identified in the reviewed literature. Applying generic ACMG/AMP 2015 combination rules: PVS1 (Strong) + PM2 (Supporting) + PP5 (Supporting) = 1 Strong + 2 Supporting, which meets the threshold for Likely Pathogenic classification.4
RAD50
Final classification
Likely Pathogenic
RAD50 c.2033_2034dup · p.Cys680HisfsTer41
RAD50
NM_005732.3:c.2033_2034dup is a frameshift 2bp duplication in exon 13 of RAD50, predicted to cause premature termination at codon 720 (p.Cys680HisfsTer41). RAD50 loss of function is an established mechanism for NBS-like disorder.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 supporting, PP5 supporting; combination = 1 strong + 2 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2PP5
Likely Pathogenic
RAD50 c.2033_2034dup
PVS1 + PM2 + PP5
→
Likely Pathogenic
1
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_005732.3 · variants mapped to exon structure
RAD50
NM_005732.3
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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47823e-06; MAF= 0.00025%, 4/1614058 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38979e-06; MAF= 0.00034%, 4/1180014 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
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
0.00025%
· 4 / 1,614,058
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
European (non-Finnish) 4 / 1,180,014 |
0.00034% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 820565)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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
Triaged references · 6 PMIDs not cited in assessment
14684699 ↗
Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility.
ONCOKB
16288216 ↗
Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract.
ONCOKB
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.
CLINVAR