About RAD50
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD50 c.2301dup, p.(Ile768HisfsTer14)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong
Frameshift variant NM_005732.3:c.2301dup (p.Ile768HisfsTer14) in exon 14 of 25, predicted to undergo nonsense-mediated decay. RAD50 loss of function is an established disease mechanism for RAD50 deficiency syndrome (PMID:32212377). Under ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene where LOF is a known mechanism meets PVS1 at strong strength.
PM2Supporting
PM2 · supporting
NM_005732.3:c.2301dupC is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes), meeting the PM2 threshold for absence from population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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; combination = 1 strong + 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 9 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005732.3:c.2301dup (p.Ile768HisfsTer14) is a frameshift duplication in exon 14 of RAD50, predicted to undergo nonsense-mediated decay. RAD50 loss of function is an established disease mechanism for RAD50 deficiency syndrome.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant.
No variant-specific functional data, clinical case reports, de novo observations, or segregation data were identified in the reviewed literature. Four RAD50 gene-level publications were reviewed but none reported this specific variant.
Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one strong criterion (PVS1) plus one supporting criterion (PM2) yields a classification of Likely Pathogenic.
No criteria match.
Met · 2
PVS1 StrongFrameshift variant NM_005732.3:c.2301dup (p.Ile768HisfsTer14) in exon 14 of 25, predicted to undergo nonsense-mediated decay. RAD50 loss of function is an established disease mechanism for RAD50 deficiency syndrome (PMID:32212377). Under ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene where LOF is a known mechanism meets PVS1 at strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift duplication at c.2301 leading to premature termination at codon 781 (I768Hfs*14)
- PTC located in exon 14 of 25
- well upstream of the last exon-exon junction
- predicting NMD
- Germline RAD50 LOF established as disease mechanism (RAD50 deficiency syndrome
- PMID:32212377)
- No population LOF enrichment concerns — variant is absent from gnomAD
Still missing
- Transcript NM_005732.3 is RefSeq Select but not MANE
- confirm this is the clinically relevant transcript
- No CSPEC/VCEP PVS1 specification for RAD50 — relying on generic PMC6185798 framework
Sources
PM2 SupportingNM_005732.3:c.2301dupC is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes), meeting the PM2 threshold for absence from population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 9 · evaluated, threshold not reached
PM1 The variant is not located in a statistically significant mutational hotspot (cancerhotspots.org), and no domain-level constraint data support localization in a critical functional domain without benign variation for RAD50 frameshift variants at codon 768. Details ▾Hide ▴
Evidence considered
- Not present in cancerhotspots.org
- No domain-specific constraint data available for RAD50 codon 768
PP3 REVEL and BayesDel scores are not applicable (variant is not a single nucleotide substitution). SpliceAI predicts no splice impact (max delta score = 0.00). HCI prior score is unavailable for RAD50. No multiple lines of in silico evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splice impact)
- REVEL/BayesDel not applicable to duplication variants
- HCI prior not supported for RAD50
Sources
PP5 The variant is absent from ClinVar. No reputable source has independently reported this variant as pathogenic. OncoKB classifies it as Likely Oncogenic in a somatic context, which does not constitute a reputable germline source report. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0 in all populations, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD populations
Sources
BS1 The variant is absent from all population databases. Allele frequency of 0 is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD populations
Sources
BS2 No evidence that this variant has been observed in a healthy adult individual with full penetrance expected at an early age, nor observed in trans with a known pathogenic variant for a dominant disorder. Such data are absent from the literature and databases. Details ▾Hide ▴
Still missing
- No observation in healthy adult controls with full penetrance disorder
BP2 No evidence that NM_005732.3:c.2301dupC has been observed in trans with a known pathogenic variant in a fully penetrant dominant disorder, or in cis with a known pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Still missing
- No phase data available
BP5 No evidence that NM_005732.3:c.2301dupC has been observed in a case with an alternate molecular basis for disease. No patient-level data are available. Details ▾Hide ▴
Still missing
- No patient-level molecular data available
BP6 No reputable source has independently reported NM_005732.3:c.2301dupC as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no benign classification from any submitter
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observation of this variant has been identified in any reviewed publication or database. No patient-specific clinical data are available. Details ▾Hide ▴
Still missing
- No de novo data available for this variant
PS3 No variant-specific functional studies for NM_005732.3:c.2301dupC were identified in the reviewed literature. Four RAD50 gene-level functional publications were reviewed (PMID:12208847, 14684699, 16288216, 21892167) but none evaluated this specific variant. Details ▾Hide ▴
Evidence considered
- Four RAD50 functional publications reviewed
- all are gene-level studies without this variant
Still missing
- No variant-specific functional assays available for NM_005732.3:c.2301dupC
PS4 No case-control or cohort studies specifically reporting NM_005732.3:c.2301dupC were identified. The variant is absent from ClinVar and COSMIC, and no publication reports it in affected individuals. Details ▾Hide ▴
Still missing
- No prevalence data in affected vs. control populations
PM6 No de novo report for NM_005732.3:c.2301dupC was identified in any reviewed publication or database. De novo evidence is required to apply PM6. Details ▾Hide ▴
Still missing
- No de novo observation reported for this variant
PP1 No family segregation data are available for NM_005732.3:c.2301dupC. Cosegregation analysis requires genotyping of multiple affected and unaffected family members. Details ▾Hide ▴
Still missing
- No segregation data available
PP4 No patient phenotype or family history information is available for the individual carrying this variant. PP4 requires a phenotype highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype data available
BS3 No variant-specific functional studies demonstrating no damaging effect for NM_005732.3:c.2301dupC were identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No variant-specific functional assays showing benign effect
BS4 No family cosegregation data are available to demonstrate lack of segregation with disease for NM_005732.3:c.2301dupC. Details ▾Hide ▴
Still missing
- No segregation data available
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a different nucleotide change at the same position producing the same amino acid change (same-residue missense comparator rule). This variant is a frameshift duplication, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per adjudication instructions — not assessed in this pass. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions in nonrepeat regions or stop-loss variants. NM_005732.3:c.2301dupC is a frameshift duplication; null variant effect is captured under PVS1. PM4 is not applicable to frameshift variants per ACMG/AMP 2015 guidance. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue (same-residue missense comparator). This variant is a frameshift, and no same-residue comparators were identified (pm5_candidates returned not_applicable). Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies specifically to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This variant is a frameshift duplication, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_005732.3:c.2301dupC is itself a truncating (frameshift) variant, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_005732.3:c.2301dupC is a frameshift duplication, not an in-frame variant. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 applies to variants for which multiple lines of computational evidence suggest no impact on the gene or gene product. The mechanism of NM_005732.3:c.2301dupC is protein truncation via frameshift, not a missense or splice alteration. SpliceAI shows no splice impact (delta=0.00) but this is not the primary mechanism, and REVEL/BayesDel are not applicable to duplication variants. BP4 is not appropriate for a null variant already evaluated under PVS1. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotides. NM_005732.3:c.2301dupC is a frameshift duplication, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires a different pathogenic missense change at the same amino acid residue. This variant is a frameshift duplication, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RAD50
- Transcript
- NM_005732.3
- Coding (HGVS c.)
- NM_005732.3:c.2301dup
- Protein (HGVS p.)
- NP_005723.2:p.(Ile768HisfsTer14)
- GRCh38
- chr5:132603392 A>AC
- GRCh37
- chr5:131939084 A>AC
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RAD50
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 REVEL and BayesDel scores are not applicable (variant is not a single nucleotide substitution). SpliceAI predicts no splice impact (max delta score = 0.00). HCI prior score is unavailable for RAD50. No multiple lines of in silico evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splice impact)
- REVEL/BayesDel not applicable to duplication variants
- HCI prior not supported for RAD50
Sources
BP4 N/ABP4 applies to variants for which multiple lines of computational evidence suggest no impact on the gene or gene product. The mechanism of NM_005732.3:c.2301dupC is protein truncation via frameshift, not a missense or splice alteration. SpliceAI shows no splice impact (delta=0.00) but this is not the primary mechanism, and REVEL/BayesDel are not applicable to duplication variants. BP4 is not appropriate for a null variant already evaluated under PVS1. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotides. NM_005732.3:c.2301dupC is a frameshift duplication, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
4 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
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PMID 12208847 ↗Cancer predisposition and hematopoietic failure in Rad50(S/S) mice.Characterized a hypomorphic Rad50 mutant mouse model (Rad50(S/S)) displaying growth defects, cancer predisposition, and hematopoietic stem cell failure. NM_005732.3:c.2301dupC was not identified in this paper.Does not name this variant
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PMID 14684699 ↗Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility.Conducted mutation screening of MRE11, RAD50, and NBN in breast and ovarian cancer families. Identified RAD50 687delT as a possible disease-associated variant. NM_005732.3:c.2301dupC was not reported.Does not name this variant
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PMID 16288216 ↗Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract.Evaluated microsatellite instability-driven mutations in 13 candidate genes in urothelial cell carcinomas. RAD50 mutations were detected in 3 of 4 MSI tumors as somatic MSI-driven events at mononucleotide repeat tracts, but NM_005732.3:c.2301dupC was not among the variants reported.Does not name this variant
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PMID 21892167 ↗The Rad50 coiled-coil domain is indispensable for Mre11 complex functions.Investigated functional domains of the Rad50 coiled-coil region in Saccharomyces cerevisiae using engineered truncation alleles. The study was performed in yeast and did not assess human RAD50 variants. NM_005732.3:c.2301dupC was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005732.3%3Ac.2301dupC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-131939084-A-AC?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-132603392-A-AC?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-132603392-A-AC
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005732.3%3Ac.2301…
- OncoKB ↗www.oncokb.org/gene/RAD50/I768Hfs*14
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD50+c.2301dup
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.