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 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
strong
Pathogenic
NM_005732.3:c.2033_2034dup is a 2bp duplication in exon 13 producing a frameshift and premature termination at codon 720 (p.Cys680HisfsTer41), well upstream of the native stop at codon 1313. NMD is expected. RAD50 loss of function is an established mechanism for NBS-like disorder (NBSLD), supported by germline disease literature. Under the ClinGen SVI PVS1 generic framework (PMC6185798), this frameshift null variant in a gene with confirmed LoF disease mechanism qualifies for PVS1 at strong strength.
NM_005732.3:c.2033_2034dup is a 2bp duplication producing p.Cys680HisfsTer41 frameshiftPremature termination at codon 720 with native stop at codon 1313NMD expected
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. In gnomAD v4.1, it is present at an allele frequency of 2.48e-6 (4/1,614,058 alleles, 0 homozygotes; grpmax FAF=7.9e-7), which is well below the 0.1% threshold for PM2. Highest subpopulation frequency is European (non-Finnish) at 3.39e-6.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD-Canada v1.0gnomAD v4.1: AF=2.48e-6 (4/1
✓
PP5
supporting
review
Pathogenic
This variant has been classified as Pathogenic in ClinVar by two independent clinical laboratories (Ambry Genetics and Labcorp Genetics/Invitae) using clinical testing criteria. Although the review status is criteria provided, single submitter (each), the consistent Pathogenic call from multiple clinical laboratories supports PP5 at the supporting level under generic ACMG/AMP.
ClinVar Variation ID 820565: Pathogenic classificationTwo clinical laboratory submissions: Ambry Genetics and Labcorp GeneticsConsistent Pathogenic classification across submitters
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified for NM_005732.3:c.2033_2034dup.
PS4
Two clinical laboratories have classified this variant as Pathogenic in ClinVar, but no case-level enrichment data (case counts vs.
PM1
Variant c.2033_2034dup is in exon 13 encoding the coiled-coil domain of RAD50, but this specific residue/region is not a statistically significant mutational hotspot in the hotspot database.
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP4
Insufficient phenotype-level specificity data for the probands carrying this variant.
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 2.48e-6 (0.00025%), far below the BA1 threshold of 1%.
BS1
The variant allele frequency of 2.48e-6 in gnomAD v4.1 is far below the BS1 threshold of 0.3%.
BS2
No data on observation of this variant in healthy adults, particularly in homozygous state, are available.
BS3
No variant-specific functional studies demonstrating no deleterious effect have been identified.
BS4
No segregation data are available to assess lack of cosegregation with disease.
BP2
No data on observation of this variant in trans with a known pathogenic variant are available.
BP5
BP5 applies when a variant is found in a case with an alternate molecular basis for disease.
BP6
No reputable source has classified this variant as benign or likely benign.
N/A · 10
PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
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