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RAD50c.2033_2034dupLikely pathogenic
Print report
Variant interpretation report

RAD50 c.2033_2034dup, p.(Cys680HisfsTer41)

NM_005732.3:c.2033_2034dup NP_005723.2:p.(Cys680HisfsTer41) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RAD50

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Strong
PVS1 · strong

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.

PM2Supporting
PM2 · supporting

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.

PP5Supporting
PP5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 6 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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%.

This variant has been classified as Pathogenic in ClinVar by two clinical laboratories (Ambry Genetics, Labcorp Genetics).

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.

Met · 3

PVS1 StrongNM_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. Details ▾Hide ▴
Evidence considered
  • NM_005732.3:c.2033_2034dup is a 2bp duplication producing p.Cys680HisfsTer41 frameshift
  • Premature termination at codon 720 with native stop at codon 1313
  • NMD expected
  • RAD50 biallelic loss of function causes NBS-like disorder (PMID:19409520
  • PMID:32212377)
  • Generic PVS1 framework (PMC6185798) applied per ClinGen SVI recommendations
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD-Canada v1.0
  • gnomAD v4.1: AF=2.48e-6 (4/1
  • 614
  • 058 alleles
  • 0 homozygotes)
  • grpmax FAF=7.9e-7
  • well below PM2 0.1% threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP5 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 820565: Pathogenic classification
  • Two clinical laboratory submissions: Ambry Genetics and Labcorp Genetics
  • Consistent Pathogenic classification across submitters
Sources
clinvar ↗

Not met · 6 · evaluated, threshold not reached

PS4 Two clinical laboratories have classified this variant as Pathogenic in ClinVar, but no case-level enrichment data (case counts vs. controls) are available. The available submissions do not meet the PS4 threshold for case-control statistical significance. Details ▾Hide ▴
Evidence considered
  • Two clinical laboratory submissions in ClinVar classify as Pathogenic
  • Insufficient case-level enumeration for PS4 statistical support
Still missing
  • No case-control or case-count enrichment data available
Sources
clinvar ↗
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. No ClinGen-defined functional domain hotspot threshold is met. Details ▾Hide ▴
Evidence considered
  • Not listed in a statistically significant mutational hotspot
  • Lies in the RAD50 coiled-coil domain but no residue-level enrichment identified
BA1 The variant allele frequency in gnomAD v4.1 is 2.48e-6 (0.00025%), far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=2.48e-6
  • well below 1% BA1 cutoff
Sources
gnomad_v4 ↗
BS1 The variant allele frequency of 2.48e-6 in gnomAD v4.1 is far below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=2.48e-6
  • well below 0.3% BS1 cutoff
Sources
gnomad_v4 ↗
BP5 BP5 applies when a variant is found in a case with an alternate molecular basis for disease. This variant has been observed in the context of RAD50-related disease (ClinVar Pathogenic classification) and no alternate molecular basis has been identified. Details ▾Hide ▴
Evidence considered
  • Variant observed in disease-relevant clinical testing context
  • No alternate molecular basis identified
BP6 No reputable source has classified this variant as benign or likely benign. ClinVar classification is Pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Pathogenic (not benign)
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo genotyping data available
PS3 No variant-specific functional studies were identified for NM_005732.3:c.2033_2034dup. The literature search returned RAD50 gene-level functional studies (mouse Rad50 models, yeast Mre11 complex studies) but none examined this specific variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional data found in available literature
Still missing
  • No variant-specific functional assay data available
PM6 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo genotyping data available
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 Insufficient phenotype-level specificity data for the probands carrying this variant. While RAD50 deficiency is associated with NBS-like disorder, specific phenotype data for individuals with c.2033_2034dup are not available. Details ▾Hide ▴
Still missing
  • Phenotype data for affected individuals not available
BS2 No data on observation of this variant in healthy adults, particularly in homozygous state, are available. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers available
BS3 No variant-specific functional studies demonstrating no deleterious effect have been identified. The literature review returned gene-level studies but none examined this specific variant for benign functional outcome. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional data demonstrating benign effect found
Still missing
  • No variant-specific functional studies available
BS4 No segregation data are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data on observation of this variant in trans with a known pathogenic variant are available. Details ▾Hide ▴
Still missing
  • No phasing data available for observation in trans
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to variants resulting in the same amino acid change as an established pathogenic missense variant. This is a frameshift variant; PS1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per assessment instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame insertions/deletions in non-repeat regions. This variant is a frameshift duplication and is assessed under PVS1; PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a same-residue missense comparator with an established pathogenic classification. This frameshift variant does not have a classic missense comparator, and the automated PM5 candidate harvest confirmed no eligible same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvest returned no same-residue candidates
Sources
pm5_candidates
PP2 N/APP2 applies to genes where missense variants are a predominant mechanism of disease with a low rate of benign missense variation. RAD50 is a gene where loss-of-function (truncating) variants are the primary disease mechanism; PP2 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 relies on multiple lines of in silico evidence (REVEL, BayesDel, splicing predictors) supporting a deleterious effect. REVEL and BayesDel are not available for non-SNV frameshift variants. SpliceAI max delta is 0.02, indicating no significant splicing impact. PP3 is not applicable for this frameshift variant. Details ▾Hide ▴
Evidence considered
  • REVEL not available for non-SNV indels
  • BayesDel not available for non-SNV indels
  • SpliceAI max delta = 0.02 (no significant splice impact predicted)
Sources
spliceai ↗
BP1 N/ABP1 applies to genes where a specific missense variant is observed when truncating variants are the only known cause of disease. RAD50 disease is caused by loss-of-function variants (truncating, frameshift, nonsense); a frameshift variant does not meet BP1 applicability criteria. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions without a known function. This variant is a frameshift duplication and is not applicable for BP3. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 relies on multiple lines of in silico evidence predicting no impact. REVEL and BayesDel are not available for non-SNV frameshift variants. SpliceAI shows no significant splicing impact (max delta=0.02), but BP4 is not designed for frameshift variants and is not applicable. Details ▾Hide ▴
Evidence considered
  • REVEL not available for non-SNV indels
  • BayesDel not available for non-SNV indels
  • SpliceAI max delta = 0.02
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a frameshift variant; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not applicable to frameshift variants. This criterion applies to de novo observation of a recessive pathogenic missense variant in trans. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RAD50
Transcript
NM_005732.3
Coding (HGVS c.)
NM_005732.3:c.2033_2034dup
Protein (HGVS p.)
NP_005723.2:p.(Cys680HisfsTer41)
GRCh38
chr5:132595635 C>CAG
GRCh37
chr5:131931327 C>CAG
ClinVar
820565

Gene diagram

Every interpreted variant in RAD50, mapped onto the exon structure of NM_005732.3. Select a row to find it on the plot.

RAD50NM_005732.3
Fetching transcript structure from UCSC…
gnomAD v4.1 4 / 1,614,058 alleles AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,614,058 alleles · 0 hom · FAF 7.9e-07
European (non-Finnish)4 / 1,180,014 3.4e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -15 bp
0.020
SpliceAI acceptor gainat -62 bp
0.010
SpliceAI donor lossat -434 bp
0.010
SpliceAI donor gainat +175 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 relies on multiple lines of in silico evidence (REVEL, BayesDel, splicing predictors) supporting a deleterious effect. REVEL and BayesDel are not available for non-SNV frameshift variants. SpliceAI max delta is 0.02, indicating no significant splicing impact. PP3 is not applicable for this frameshift variant. Details ▾Hide ▴
Evidence considered
  • REVEL not available for non-SNV indels
  • BayesDel not available for non-SNV indels
  • SpliceAI max delta = 0.02 (no significant splice impact predicted)
Sources
spliceai ↗
BP4 N/ABP4 relies on multiple lines of in silico evidence predicting no impact. REVEL and BayesDel are not available for non-SNV frameshift variants. SpliceAI shows no significant splicing impact (max delta=0.02), but BP4 is not designed for frameshift variants and is not applicable. Details ▾Hide ▴
Evidence considered
  • REVEL not available for non-SNV indels
  • BayesDel not available for non-SNV indels
  • SpliceAI max delta = 0.02
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a frameshift variant; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Cancer predisposition and hematopoietic failure in Rad50(S/S) mice.
    Bender et al. (2002) describe cancer predisposition and hematopoietic failure in Rad50(S/S) hypomorphic mutant mice. The study demonstrated that Rad50 hypomorphic mice exhibit growth defects, cancer predisposition, and progressive bone marrow failure due to hematopoietic stem cell depletion. NM_005732.3:c.2033_2034dup was not identified in this paper.
    Does not name this variant
    PMID 12208847 ↗
  • Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility.
    Heikkinen et al. (2003) performed mutation screening of MRE11 complex genes (MRE11, RAD50, NBN) in Finnish breast and ovarian cancer families. The study identified RAD50 missense variants in breast/ovarian cancer cohorts but did not describe NM_005732.3:c.2033_2034dup. This is a brief letter to the editor with limited content.
    Does not name this variant
    PMID 14684699 ↗
  • Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract.
    This study evaluated microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas. RAD50 was screened along with other DNA repair genes. NM_005732.3:c.2033_2034dup was not identified in this paper.
    Does not name this variant
    PMID 16288216 ↗
  • The Rad50 coiled-coil domain is indispensable for Mre11 complex functions.
    Hohl et al. (2011) studied the Rad50 coiled-coil domain in S. cerevisiae, demonstrating that the coiled-coil and hook domains are indispensable for Mre11 complex functions including meiotic DSB formation, telomere maintenance, and sister chromatid recombination. This is a yeast model study; NM_005732.3:c.2033_2034dup was not identified.
    Does not name this variant
    PMID 21892167 ↗
  • Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.
    Waltes R et al. · 2009
    Waltes et al. (2009) describe the first patient with RAD50 deficiency presenting as NBS-like disorder. The proband is compound heterozygous for c.3277C>T (p.R1093X) in exon 21 and c.3939A>T (p.X1313YextX*66) in exon 25. Functional studies demonstrated absent RAD50 protein, impaired MRN foci formation, radiosensitivity, and defective ATM signaling in patient cells. NM_005732.3:c.2033_2034dup was not identified in this paper.
    Does not name this variant
    PMID 19409520 ↗
    Quoted passage
    Sequence analysis of the entire coding region of RAD50 at cDNA (LCL) and gDNA levels for both lymphocytes and fibroblasts revealed compound heterozygosity for mutations that are predicted to be deleterious (Figure 1D). The maternally inherited mutation (c.3277C→T; p.R1093X) is located in exon 21 and creates a premature termination codon (Figure 1D, upper panel). The paternally inherited mutation (c.3939A→T), located in exon 25, affects the RAD50 stop codon by changing the ochre triplet at codon 1313 into a tyrosine codon (Figure 1D, middle).

    Mutations described in Results: Mutations in the RAD50 Gene section; compound heterozygosity for c.3277C>T and c.3939A>T

  • 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.
    Hampel H et al. · 2015
    Hampel et al. (2015) present an ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. This is a clinical practice guideline document that does not report individual variants. NM_005732.3:c.2033_2034dup was not identified.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 4 / 1,614,058 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 2 Pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.