About RAD50
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD50 c.221A>C, p.(Gln74Pro)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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Criteria may be applied incorrectly, sources may be misread, and a
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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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (3/1,594,676 alleles, AF=0.000000188, grpmax FAF=6.9e-7), well below the 0.1% PM2 threshold. All three alleles are in the European (non-Finnish) population with zero homozygotes.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
NM_005732.3:c.221A>C is a missense variant in RAD50, a gene for which the established germline disease mechanism is biallelic loss-of-function. RAD50 deficiency (OMIM #613078) is caused by truncating variants and other null alleles. A missense variant in a gene where truncating variants are the primary disease mechanism carries lower prior probability of pathogenicity.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign interpretation. REVEL score is 0.263 (below the commonly applied 0.5 threshold for pathogenicity), BayesDel score is -0.354 (negative/benign-leaning), and SpliceAI predicts no splice-altering effect (max delta score 0.01).
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP1 supporting benign, BP4 supporting benign; combination = 1 moderate + 2 supporting benign, which maps to Likely Benign.
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
3 / 1,594,676 alleles
gnomAD v4.1: 3 / 1,594,676 alleles. Recorded AF 1.88126e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD50 encodes a component of protein complex critical to DNA double-stranded-break end processing. Select germline mutations of RAD50 predispose to br
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.
26 criteria with recorded statuses: 3 met · 21 not met · 0 not assessed · 2 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.221A>C (p.Gln74Pro) is a missense variant in RAD50, a gene in which biallelic loss-of-function variants cause RAD50 deficiency (OMIM #613078), an autosomal recessive disorder of DNA double-strand break repair.
This variant is absent from gnomAD v2.1 and observed at extremely low frequency in gnomAD v4.1 (3/1,594,676 total alleles, AF=1.88e-6, 0 homozygotes), with all three alleles restricted to the European (non-Finnish) subpopulation (grpmax FAF=6.9e-7). This extreme rarity meets PM2 at moderate strength.
REVEL (0.263), BayesDel (-0.354), and SpliceAI (max delta 0.01) all predict no damaging effect on protein function or splicing, meeting BP4 at supporting benign strength.
As a missense variant in a gene where truncating variants are the established disease mechanism, BP1 applies at supporting benign strength.
ClinVar reports this variant as Uncertain Significance (variation ID 1053169) based on two clinical laboratory submissions (Ambry Genetics and Invitae/Labcorp); no expert panel review is available. This does not meet criteria for PP5 or BP6, as neither pathogenic nor benign consensus has been reached.
No variant-specific functional studies, de novo observations, case-control data, segregation data, or published case reports were identified for this variant. OncoKB reports unknown oncogenic effect with no curated functional evidence.
Overall, the evidence profile consists of one moderate pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4). The net classification is Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.
No criteria match.
Met · 3
PM2 ModerateThis variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (3/1,594,676 alleles, AF=0.000000188, grpmax FAF=6.9e-7), well below the 0.1% PM2 threshold. All three alleles are in the European (non-Finnish) population with zero homozygotes. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 alleles (absent). gnomAD v4.1: 3 alleles total (AF=1.88e-6)
- all in NFE subpopulation (AF=2.58e-6)
- 0 homozygotes
- grpmax FAF=6.9e-7.
Sources
BP1 SupportingNM_005732.3:c.221A>C is a missense variant in RAD50, a gene for which the established germline disease mechanism is biallelic loss-of-function. RAD50 deficiency (OMIM #613078) is caused by truncating variants and other null alleles. A missense variant in a gene where truncating variants are the primary disease mechanism carries lower prior probability of pathogenicity. Details ▾Hide ▴
Evidence considered
- RAD50 germline disease mechanism is loss-of-function. PVS1 gene context confirmed LoF as the established mechanism via literature supporting biallelic null variants in RAD50 deficiency.
Sources
pvs1_gene_context
BP4 SupportingMultiple lines of computational evidence support a benign interpretation. REVEL score is 0.263 (below the commonly applied 0.5 threshold for pathogenicity), BayesDel score is -0.354 (negative/benign-leaning), and SpliceAI predicts no splice-altering effect (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- REVEL: 0.263 (no deleterious prediction). BayesDel: -0.354 (benign). SpliceAI: max delta 0.01 (no splice impact).
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternate nucleotide change at c.221 resulting in the same amino acid change (p.Gln74Pro) has been established as pathogenic. PS1 requires a different nucleotide substitution at the same codon that produces the same missense change and is known to be pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar reviewed
- no alternate nucleotide change at c.221 with established pathogenicity identified.
Sources
PS2 No de novo occurrence data available for this variant. PS2 requires confirmation of a de novo variant with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PS3 No variant-specific experimental functional data identified. OncoKB reports unknown oncogenic effect with no variant-level functional evidence. No publications with functional characterization of NM_005732.3:c.221A>C (p.Gln74Pro) were identified. The available in silico predictions (REVEL 0.263, BayesDel -0.354) suggest no damaging effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. No experimental functional studies for p.Gln74Pro identified in literature.
Still missing
- No functional studies have tested this variant.
Sources
PS4 No case-control data demonstrating statistically significant enrichment of this variant in affected individuals. ClinVar records two clinical laboratory submissions (both VUS), but no case counts, odds ratios, or statistical comparison against controls is available. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical lab submissions (Ambry
- Invitae)
- both VUS
- no case-control statistics available.
Still missing
- No case-control or cohort data available.
Sources
PM1 This variant does not lie in a statistically significant hotspot per cancerhotspots.org, and there is insufficient evidence that residue 74 resides in a well-established critical functional domain without benign variation. While position 74 may be within the N-terminal ABC-ATPase domain of RAD50, no domain-level PM1 framework or CSPEC guidance is available to support application. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant
- no CSPEC/VCEP domain framework for RAD50.
Still missing
- No RAD50-specific domain-level PM1 criteria available.
PM5 No pathogenic missense variant at amino acid position 74 with a different amino acid change was identified. The PM5 candidate pipeline found zero same-residue comparator variants with pathogenic classification in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvest returned 0 same-residue candidates
- recommendation level was not_applicable.
Sources
pm5_candidates
PM6 No de novo report available for this variant. PM6 requires a de novo observation with confirmed maternity and paternity, without confirmation that the variant occurred de novo. Details ▾Hide ▴
Still missing
- No de novo testing performed or reported.
PP1 No co-segregation data available. PP1 requires demonstration that the variant co-segregates with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 RAD50 disease (RAD50 deficiency, OMIM #613078) is primarily caused by biallelic loss-of-function variants. Missense variants are not the established common disease mechanism, and there is insufficient evidence that RAD50 has a low rate of benign missense variation (no gene-specific missense constraint z-score available). Details ▾Hide ▴
Evidence considered
- RAD50 disease mechanism is loss-of-function (biallelic truncating variants)
- missense is not the primary pathogenic mechanism.
Still missing
- No RAD50 missense constraint metric available.
Sources
pvs1_gene_context
PP3 Multiple lines of computational evidence suggest no damaging effect. REVEL score is 0.263 (below 0.5 pathogenic threshold), BayesDel score is -0.354 (benign-leaning), and SpliceAI predicts no splice impact (max delta 0.01). These results do not support a deleterious effect and instead support benign interpretation (see BP4). Details ▾Hide ▴
Evidence considered
- REVEL: 0.263 (damaging threshold ≥0.5 not met). BayesDel: -0.354 (negative/benign). SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
PP4 No patient phenotype or family history data available for review. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No proband phenotype or family history provided.
PP5 ClinVar reports this variant as Uncertain Significance (2 clinical laboratories), not pathogenic. No expert panel review available (1-star review status: criteria provided, single submitter). PP5 requires a reputable source to have classified the variant as pathogenic when independent evidence is not available for review. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 1053169: VUS
- 2 submitters (Ambry
- Invitae)
- review status: criteria provided
- single submitter (1 star)
- no expert panel.
Sources
BA1 The variant allele frequency in gnomAD v4.1 is 0.000019% (3/1,594,676 alleles), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.88e-6 (0.000019%)
- well below 1% BA1 threshold.
Sources
BS1 The variant allele frequency in gnomAD v4.1 is 0.000019% (3/1,594,676 alleles; grpmax FAF=6.9e-7), far below the 0.3% BS1 threshold for a non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.88e-6
- grpmax FAF=6.9e-7
- well below 0.3% BS1 threshold.
Sources
BS2 While this variant is observed in gnomAD (3 alleles in presumably healthy population controls), no specific healthy adult individual with confirmed phenotype has been documented. BS2 requires an explicit observation of the variant in a healthy adult individual where full penetrance is expected at an early age. The mere presence in population databases, especially at extremely low frequency, does not satisfy BS2 without confirmatory phenotype data. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 3 alleles at AF=1.88e-6
- no specific healthy adult phenotype confirmation.
Still missing
- No healthy adult observation with confirmed phenotype available.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate that this variant has no damaging effect on protein function or splicing. OncoKB reports unknown oncogenic effect with no variant-specific functional characterization. In silico predictions (REVEL 0.263, BayesDel -0.354) are computational, not functional data. Details ▾Hide ▴
Evidence considered
- No experimental functional studies identified. OncoKB: no variant-specific reviewed functional evidence.
Still missing
- No functional experimental data for this variant.
Sources
BS4 No segregation data available showing lack of co-segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
- No phasing or trans/cis data available.
BP5 No observation of this variant in a case where an alternate molecular basis for disease has been identified. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnoses in carriers.
BP6 ClinVar reports this variant as Uncertain Significance (2 clinical laboratories), not benign or likely benign. BP6 requires a reputable source to have classified the variant as benign when independent evidence is not available for review. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 1053169: VUS classification
- no benign or likely benign assertion from any submitter.
Sources
PS5 No established pathogenic variant with the same amino acid change (p.Gln74Pro) has been reported independently. PS5 requires that the identical amino acid change, regardless of nucleotide change, be previously established as pathogenic. Details ▾Hide ▴
Evidence considered
- No pathogenic classification for p.Gln74Pro in ClinVar or literature.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_005732.3:c.221A>C is a missense variant (p.Gln74Pro) in exon 3 of 25. It does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) required for generic PVS1 framework assessment per ClinGen SVI recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a predicted null variant
- PVS1 variant assessment confirmed variant bucket 'other' and apply_generic_pvs1_framework=false.
Sources
BP7 N/ANot applicable: NM_005732.3:c.221A>C is a missense (nonsynonymous) variant, not a synonymous variant. BP7 applies exclusively to silent/synonymous variants. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RAD50
- Transcript
- NM_005732.3
- Coding (HGVS c.)
- NM_005732.3:c.221A>C
- Protein (HGVS p.)
- NP_005723.2:p.(Gln74Pro)
- GRCh38
- chr5:132575784 A>C
- GRCh37
- chr5:131911476 A>C
- ClinVar
- 1053169
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
3 / 1,594,676 alleles
AF 1.88e-06 · 0 homozygotes · FAF 6.9e-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 1.9e-06 · 3 / 1,594,676 alleles · 0 hom · FAF 6.9e-07
| European (non-Finnish)3 / 1,162,284 | 2.6e-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= 1.88126e-06; MAF= 0.00019%, 3/1594676 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.58112e-06; MAF= 0.00026%, 3/1162284 alleles, homozygotes = 0); grpmax FAF= 6.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.263
- BayesDel
- -0.354
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign interpretation. REVEL score is 0.263 (below the commonly applied 0.5 threshold for pathogenicity), BayesDel score is -0.354 (negative/benign-leaning), and SpliceAI predicts no splice-altering effect (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- REVEL: 0.263 (no deleterious prediction). BayesDel: -0.354 (benign). SpliceAI: max delta 0.01 (no splice impact).
Sources
PP3 Multiple lines of computational evidence suggest no damaging effect. REVEL score is 0.263 (below 0.5 pathogenic threshold), BayesDel score is -0.354 (benign-leaning), and SpliceAI predicts no splice impact (max delta 0.01). These results do not support a deleterious effect and instead support benign interpretation (see BP4). Details ▾Hide ▴
Evidence considered
- REVEL: 0.263 (damaging threshold ≥0.5 not met). BayesDel: -0.354 (negative/benign). SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
BP7 N/ANot applicable: NM_005732.3:c.221A>C is a missense (nonsynonymous) variant, not a synonymous variant. BP7 applies exclusively to silent/synonymous variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.263. BayesDel score = -0.354261.
1 paper record 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
-
PMID 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.Hampel H et al. · 2015This is an ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. It provides general criteria for when to refer patients for cancer genetic consultation. RAD50 is not discussed in this paper, and NM_005732.3:c.221A>C 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
3 / 1,594,676 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
2 Uncertain significance
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/variation/1053169/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-131911476-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-132575784-A-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-132575784-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005732.3%3Ac.221A…
- OncoKB ↗www.oncokb.org/gene/RAD50/Q74P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD50+c.221A%3EC
- 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
This variant is present in gnomAD v4.1 (AF= 1.88126e-06; MAF= 0.00019%, 3/1594676 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.58112e-06; MAF= 0.00026%, 3/1162284 alleles, homozygotes = 0); grpmax FAF= 6.9e-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 Uncertain significance (2 clinical laboratories). (ClinVarID = 1053169)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.263. BayesDel score = -0.354261.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD50 encodes a component of protein complex critical to DNA double-stranded-break end processing. Select germline mutations of RAD50 predispose to br
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.