NBNc.657_661delPathogenic

Print report

Variant interpretation report

NBN c.657_661del, p.(Lys219AsnfsTer16)

NM_002485.4:c.657_661del NP_002476.2:p.(Lys219AsnfsTer16) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About NBN

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 strong (pathogenic) · 2 moderate (pathogenic) · 3 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 38 Pathogenic · 1 risk factor
Pipeline record: 12 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_002485.4:c.657_661del is a frameshift deletion in exon 6 of 16 that introduces a premature termination codon at position 234 (p.Lys219AsnfsTer16), well upstream of the final exon-exon junction, predicting nonsense-mediated decay. NBN loss of function is a well-established mechanism for Nijmegen breakage syndrome (autosomal recessive). Under PMC6185798 generic PVS1 framework, frameshift variants in LoF-eligible genes warrant PVS1 at full strength. Although internal translation initiation can produce a partially functional p70 fragment retaining the MRE11 interaction domain (PMID:11279524), this does not rescue NMD of the primary transcript and the allele remains disease-causing when homozygous.
PS3 (moderate): Functional characterization of the 657del5 NBS1 allele by Maser et al. (PMID:11279524) demonstrated that the variant produces two distinct protein products: a 26-kD N-terminal fragment (NBS1p26) containing FHA/BRCT domains but lacking the MRE11 interaction domain, and a 70-kD protein (NBS1p70) generated via internal translation initiation that retains the MRE11 interaction domain but lacks the N-terminal FHA/BRCT domains. NBS1p70 partially restores MRE11 complex nuclear localization but does not confer full function; NBS 657del5 LCLs exhibit radioresistant DNA synthesis. This is a single study with variant-specific functional data qualifying for moderate-strength PS3.
PS4 (strong): The c.657_661del variant is highly enriched in affected individuals across multiple independent studies. In recessive NBS, approximately 90% of patients are homozygous for this founder allele (PMID:10799436, PMID:11093281). In heterozygous cancer risk, Cybulski et al. (PMID:14973119) reported OR=16 (P<0.0001) for familial prostate cancer and OR=3.9 (P=0.01) for nonfamilial prostate cancer versus 0.6% population controls. Ciara et al. (PMID:19908051) reported OR=4.86 (P=0.0028) for medulloblastoma. The variant is absent from gnomAD-Canada and at very low frequency globally (AF ~0.02%), further supporting strong enrichment in disease cohorts.
PM1 (supporting): The c.657_661del frameshift truncates nibrin at codon 219, removing the MRE11 interaction domain (aa 433-754) from the primary p26 protein product. The MRE11 interaction domain is a well-characterized critical functional domain essential for DNA double-strand break repair complex formation. Although internal translation initiation produces a p70 fragment retaining this domain, the frameshift removes the domain from the canonical protein product.
PM2 (supporting): NM_002485.4:c.657_661del is present at very low frequency in population databases: gnomAD v2.1 AF=0.000202 (0.0202%, 57/282132 alleles), gnomAD v4.1 AF=0.000225 (0.0225%, 363/1613090 alleles), grpmax FAF=0.000297. No homozygotes observed. Absent from gnomAD-Canada. The frequency falls below the 0.1% PM2 threshold for a rare variant.
PP1 (moderate): Co-segregation of c.657_661del with disease has been demonstrated in multiple families. In the NBS registry study (PMID:10799436), multiple sibships showed homozygous affected individuals (e.g., patients 1-2, 3-4-5-6, 9-10). In prostate cancer families (PMID:14973119), the 657del5 mutation was present in both affected males in each of 4 tested families, and LOH of the wild-type allele was observed in 7/8 prostate tumors from carriers. In medulloblastoma (PMID:19908051), heterozygous carriers were identified in 7/104 patients.
PP5 (supporting): NM_002485.4:c.657_661del is classified as Pathogenic in ClinVar (Variation ID 6940) by 38 clinical laboratories. While the review status is criteria provided, single submitter, the 38-lab consensus with consistent Pathogenic classification across multiple independent clinical laboratories constitutes reputable source evidence.

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: 7 Benign evidence criteria: 0

Pathogenic criteria applied · 7

PVS1Very strong

PVS1 · very strong

NM_002485.4:c.657_661del is a frameshift deletion in exon 6 of 16 that introduces a premature termination codon at position 234 (p.Lys219AsnfsTer16), well upstream of the final exon-exon junction, predicting nonsense-mediated decay. NBN loss of function is a well-established mechanism for Nijmegen breakage syndrome (autosomal recessive). Under PMC6185798 generic PVS1 framework, frameshift variants in LoF-eligible genes warrant PVS1 at full strength. Although internal translation initiation can produce a partially functional p70 fragment retaining the MRE11 interaction domain (PMID:11279524), this does not rescue NMD of the primary transcript and the allele remains disease-causing when homozygous.

PS3Moderate

PS3 · moderate

Functional characterization of the 657del5 NBS1 allele by Maser et al. (PMID:11279524) demonstrated that the variant produces two distinct protein products: a 26-kD N-terminal fragment (NBS1p26) containing FHA/BRCT domains but lacking the MRE11 interaction domain, and a 70-kD protein (NBS1p70) generated via internal translation initiation that retains the MRE11 interaction domain but lacks the N-terminal FHA/BRCT domains. NBS1p70 partially restores MRE11 complex nuclear localization but does not confer full function; NBS 657del5 LCLs exhibit radioresistant DNA synthesis. This is a single study with variant-specific functional data qualifying for moderate-strength PS3.

PS4Strong

PS4 · strong

The c.657_661del variant is highly enriched in affected individuals across multiple independent studies. In recessive NBS, approximately 90% of patients are homozygous for this founder allele (PMID:10799436, PMID:11093281). In heterozygous cancer risk, Cybulski et al. (PMID:14973119) reported OR=16 (P<0.0001) for familial prostate cancer and OR=3.9 (P=0.01) for nonfamilial prostate cancer versus 0.6% population controls. Ciara et al. (PMID:19908051) reported OR=4.86 (P=0.0028) for medulloblastoma. The variant is absent from gnomAD-Canada and at very low frequency globally (AF ~0.02%), further supporting strong enrichment in disease cohorts.

PM1Supporting

PM1 · supporting

The c.657_661del frameshift truncates nibrin at codon 219, removing the MRE11 interaction domain (aa 433-754) from the primary p26 protein product. The MRE11 interaction domain is a well-characterized critical functional domain essential for DNA double-strand break repair complex formation. Although internal translation initiation produces a p70 fragment retaining this domain, the frameshift removes the domain from the canonical protein product.

PM2Supporting

PM2 · supporting

NM_002485.4:c.657_661del is present at very low frequency in population databases: gnomAD v2.1 AF=0.000202 (0.0202%, 57/282132 alleles), gnomAD v4.1 AF=0.000225 (0.0225%, 363/1613090 alleles), grpmax FAF=0.000297. No homozygotes observed. Absent from gnomAD-Canada. The frequency falls below the 0.1% PM2 threshold for a rare variant.

PP1Moderate

PP1 · moderate

Co-segregation of c.657_661del with disease has been demonstrated in multiple families. In the NBS registry study (PMID:10799436), multiple sibships showed homozygous affected individuals (e.g., patients 1-2, 3-4-5-6, 9-10). In prostate cancer families (PMID:14973119), the 657del5 mutation was present in both affected males in each of 4 tested families, and LOH of the wild-type allele was observed in 7/8 prostate tumors from carriers. In medulloblastoma (PMID:19908051), heterozygous carriers were identified in 7/104 patients.

PP5Supporting

PP5 · supporting

NM_002485.4:c.657_661del is classified as Pathogenic in ClinVar (Variation ID 6940) by 38 clinical laboratories. While the review status is criteria provided, single submitter, the 38-lab consensus with consistent Pathogenic classification across multiple independent clinical laboratories constitutes reputable source evidence.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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 very strong, PS3 moderate, PS4 strong, PM1 supporting, PM2 supporting, PP1 moderate, PP5 supporting; combination = 1 very strong + 1 strong + 2 moderate + 3 supporting, which maps to Pathogenic.

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

363 / 1,613,090 alleles

gnomAD v4.1: 363 / 1,613,090 alleles. Recorded AF 0.000225034. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000202033; MAF= 0.02020%, 57/282132 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000403808; MAF= 0.04038%, 52/128774 alleles, homozygotes = 0); grpmax FAF= 0.0002965.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0003256975355553143, 6/18422 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

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

39 reported laboratory submissions

38 Pathogenic · 1 risk factor. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → 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.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

6 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55370851, n = 6 times).

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.

28 criteria with recorded statuses: 7 met · 9 not met · 3 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

PVS1 (very strong): NM_002485.4:c.657_661del is a frameshift deletion introducing a premature termination codon (p.Lys219AsnfsTer16) in exon 6 of 16, predicting NMD. NBN loss of function is a well-established mechanism for Nijmegen breakage syndrome.

PS3 (moderate): Functional characterization demonstrated the 657del5 allele produces a truncated p26 fragment lacking the MRE11 interaction domain and a partially functional p70 fragment via internal translation initiation; NBS cells exhibit radioresistant DNA synthesis, indicating impaired S-phase checkpoint.

PS4 (strong): The variant is highly enriched in affected individuals. Approximately 90% of NBS patients are homozygous for this allele. Case-control studies demonstrate significantly elevated odds ratios: familial prostate cancer OR=16 (P<0.0001), medulloblastoma OR=4.86 (P=0.0028).

PM1 (supporting): The frameshift truncation at codon 219 removes the MRE11 interaction domain (aa 433-754), a critical functional domain for DNA double-strand break repair complex formation.

PM2 (supporting): Extremely low population frequency (gnomAD v2.1 AF=0.0202%, v4.1 AF=0.0225%), no homozygotes observed, and absent from gnomAD-Canada.

PP1 (moderate): Co-segregation demonstrated in multiple families for both NBS (recessive) and cancer predisposition, with LOH of wild-type allele in 7/8 prostate tumors from carriers.

PP5 (supporting): Classified as Pathogenic by 38 clinical laboratories in ClinVar (Variation ID 6940).

The overall classification supports Pathogenic using generic ACMG/AMP 2015 combination rules: 1 very strong (PVS1) + 1 strong (PS4) + 1 moderate (PS3) + 1 moderate (PP1) + 3 supporting (PM1, PM2, PP5) far exceeds the threshold for Pathogenic classification.

Met · 7

PVS1 Very strongNM_002485.4:c.657_661del is a frameshift deletion in exon 6 of 16 that introduces a premature termination codon at position 234 (p.Lys219AsnfsTer16), well upstream of the final exon-exon junction, predicting nonsense-mediated decay. NBN loss of function is a well-established mechanism for Nijmegen breakage syndrome (autosomal recessive). Under PMC6185798 generic PVS1 framework, frameshift variants in LoF-eligible genes warrant PVS1 at full strength. Although internal translation initiation can produce a partially functional p70 fragment retaining the MRE11 interaction domain (PMID:11279524), this does not rescue NMD of the primary transcript and the allele remains disease-causing when homozygous. Details ▾Hide ▴

Evidence considered

Frameshift deletion c.657_661del in exon 6/16 creates PTC at codon 234
predicting NMD
NBN is a well-established germline LoF disease gene (Nijmegen breakage syndrome
autosomal recessive)
Internal translation initiation producing p70 is a hypomorphic rescue mechanism that does not negate PVS1

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentPMID:11279524 ↗PMID:10799436 ↗PMID:11093281 ↗

PS3 ModerateFunctional characterization of the 657del5 NBS1 allele by Maser et al. (PMID:11279524) demonstrated that the variant produces two distinct protein products: a 26-kD N-terminal fragment (NBS1p26) containing FHA/BRCT domains but lacking the MRE11 interaction domain, and a 70-kD protein (NBS1p70) generated via internal translation initiation that retains the MRE11 interaction domain but lacks the N-terminal FHA/BRCT domains. NBS1p70 partially restores MRE11 complex nuclear localization but does not confer full function; NBS 657del5 LCLs exhibit radioresistant DNA synthesis. This is a single study with variant-specific functional data qualifying for moderate-strength PS3. Details ▾Hide ▴

Evidence considered

Direct protein characterization of 657del5 allele: NBS1p26 lacks MRE11 interaction
NBS1p70 retains MRE11 interaction but lacks FHA/BRCT domains
NBS1p70 partially restores MRE11 complex nuclear localization but fails to restore S-phase checkpoint (radioresistant DNA synthesis)
Demonstrates the 657del5 allele encodes a hypomorphic rather than null product

Still missing

Single study
no independent replication of functional findings from another lab

Sources

PMID:11279524 ↗

PS4 StrongThe c.657_661del variant is highly enriched in affected individuals across multiple independent studies. In recessive NBS, approximately 90% of patients are homozygous for this founder allele (PMID:10799436, PMID:11093281). In heterozygous cancer risk, Cybulski et al. (PMID:14973119) reported OR=16 (P<0.0001) for familial prostate cancer and OR=3.9 (P=0.01) for nonfamilial prostate cancer versus 0.6% population controls. Ciara et al. (PMID:19908051) reported OR=4.86 (P=0.0028) for medulloblastoma. The variant is absent from gnomAD-Canada and at very low frequency globally (AF ~0.02%), further supporting strong enrichment in disease cohorts. Details ▾Hide ▴

Evidence considered

90% of NBS patients homozygous for 657del5 founder allele (PMID:10799436
PMID:11093281)
Familial prostate cancer OR=16
P<0.0001 (PMID:14973119)
Nonfamilial prostate cancer OR=3.9
P=0.01 (PMID:14973119)
Medulloblastoma OR=4.86
P=0.0028 (PMID:19908051)
Multiple independent case-control studies across different cancer types

Sources

PMID:10799436 ↗PMID:11093281 ↗PMID:14973119 ↗PMID:19908051 ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM1 SupportingThe c.657_661del frameshift truncates nibrin at codon 219, removing the MRE11 interaction domain (aa 433-754) from the primary p26 protein product. The MRE11 interaction domain is a well-characterized critical functional domain essential for DNA double-strand break repair complex formation. Although internal translation initiation produces a p70 fragment retaining this domain, the frameshift removes the domain from the canonical protein product. Details ▾Hide ▴

Evidence considered

Truncation at codon 219 removes MRE11 interaction domain (aa 433-754) from primary protein product
MRE11 interaction domain is critical for DSB repair complex formation
Domain disruption is supported by functional characterization in PMID:11279524

Sources

PMID:11279524 ↗PMID:18606567 ↗

PM2 SupportingNM_002485.4:c.657_661del is present at very low frequency in population databases: gnomAD v2.1 AF=0.000202 (0.0202%, 57/282132 alleles), gnomAD v4.1 AF=0.000225 (0.0225%, 363/1613090 alleles), grpmax FAF=0.000297. No homozygotes observed. Absent from gnomAD-Canada. The frequency falls below the 0.1% PM2 threshold for a rare variant. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.0202% (57/282132)
no homozygotes
gnomAD v4.1 AF=0.0225% (363/1613090)
Absent from gnomAD-Canada
Frequency well below PM2 <0.1% threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP1 ModerateCo-segregation of c.657_661del with disease has been demonstrated in multiple families. In the NBS registry study (PMID:10799436), multiple sibships showed homozygous affected individuals (e.g., patients 1-2, 3-4-5-6, 9-10). In prostate cancer families (PMID:14973119), the 657del5 mutation was present in both affected males in each of 4 tested families, and LOH of the wild-type allele was observed in 7/8 prostate tumors from carriers. In medulloblastoma (PMID:19908051), heterozygous carriers were identified in 7/104 patients. Details ▾Hide ▴

Evidence considered

Multiple NBS sibships with co-segregation of homozygous 657del5 and disease (PMID:10799436)
4 prostate cancer families with co-segregation in affected males (PMID:14973119)
LOH of wild-type allele in 7/8 tumors from carriers
demonstrating functional hemizygosity

Sources

PMID:10799436 ↗PMID:14973119 ↗PMID:19908051 ↗

PP5 SupportingNM_002485.4:c.657_661del is classified as Pathogenic in ClinVar (Variation ID 6940) by 38 clinical laboratories. While the review status is criteria provided, single submitter, the 38-lab consensus with consistent Pathogenic classification across multiple independent clinical laboratories constitutes reputable source evidence. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 6940: Pathogenic by 38 clinical laboratories
Consistent classification across independent clinical laboratories
1 submitter classifies as risk factor

Sources

clinvar ↗

Not met · 9 · evaluated, threshold not reached

PS2 No de novo occurrence data was identified for NM_002485.4:c.657_661del in any reviewed publication. NBS is an autosomal recessive condition and this variant typically segregates from heterozygous carrier parents. Details ▾Hide ▴

Still missing

No de novo testing data available in reviewed literature

PM6 No de novo occurrence of NM_002485.4:c.657_661del was identified in any reviewed publication. The variant is a well-known founder allele segregating in families with heterozygous carrier parents. Details ▾Hide ▴

Still missing

No de novo testing data available

PP3 Multiple lines of computational evidence do not support a damaging effect. SpliceAI predicts no splicing impact (max delta=0.0). REVEL and BayesDel are not applicable to deletion variants. HCI prior is not available for NBN. No in silico evidence supports pathogenicity for this frameshift variant beyond what PVS1 already captures. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0
no predicted splice impact
REVEL/BayesDel not applicable to deletion variants
HCI prior not available for NBN

Sources

spliceai ↗

BA1 Allele frequency is far below the BA1 threshold. Maximum population frequency is 0.000404 (0.04%) in European non-Finnish gnomAD v2.1, not exceeding the 1% BA1 cutoff. Details ▾Hide ▴

Evidence considered

Maximum population AF = 0.0404% (NFE
gnomAD v2.1)
BA1 threshold is >1%
variant frequency is 25-fold below this

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Allele frequency is below the BS1 threshold. Maximum population frequency is 0.000404 (0.04%) in European non-Finnish gnomAD v2.1, not exceeding the 0.3% BS1 cutoff. Details ▾Hide ▴

Evidence considered

Maximum population AF = 0.0404% (NFE
gnomAD v2.1)
BS1 threshold is >0.3%
variant frequency is ~7-fold below this

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 Well-established functional studies do not show a benign effect. The variant-specific functional characterization by Maser et al. (PMID:11279524) demonstrates that the 657del5 allele produces aberrant protein products (p26 lacking MRE11 interaction; p70 with partial function), and cells exhibit radioresistant DNA synthesis. These findings are consistent with a damaging, not benign, functional effect. Details ▾Hide ▴

Evidence considered

657del5 produces p26 lacking MRE11 interaction domain and p70 with partial function
NBS 657del5 LCLs exhibit radioresistant DNA synthesis (S-phase checkpoint defect)
Functional evidence is consistent with damaging effect
not benign

Sources

PMID:11279524 ↗

BS4 Lack of segregation is not observed. Multiple studies demonstrate co-segregation of c.657_661del with disease in NBS families (PMID:10799436), prostate cancer families (PMID:14973119), and medulloblastoma cases (PMID:19908051). Details ▾Hide ▴

Evidence considered

Co-segregation with NBS phenotype in multiple families (PMID:10799436)
Co-segregation in prostate cancer families (PMID:14973119)
No evidence of non-segregation identified

Sources

PMID:10799436 ↗PMID:14973119 ↗PMID:19908051 ↗

BP6 BP6 applies when a reputable source reports the variant as benign. ClinVar classifies NM_002485.4:c.657_661del as Pathogenic (38 clinical laboratories), not benign. Details ▾Hide ▴

Evidence considered

ClinVar: Pathogenic by 38 labs
1 risk factor
no benign classifications

Sources

clinvar ↗

PS5 PS5 applies when a reputable source reports the variant as pathogenic but the evidence is not available for independent evaluation. Extensive evidence is available for NM_002485.4:c.657_661del including multiple full-text publications, population data, and functional studies, enabling independent evaluation. Details ▾Hide ▴

Evidence considered

Full evidence package available for independent evaluation
PS5 is not the appropriate criterion

Not assessed · 3 · no assessment recorded

PP4 PP4 requires the specific patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No individual patient phenotype data was provided for this case. The variant is strongly associated with Nijmegen breakage syndrome and cancer predisposition, but without the proband's specific clinical presentation, PP4 cannot be assessed. Details ▾Hide ▴

Still missing

No proband phenotype/family history data available

BP2 BP2 requires observation of the variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant. No systematic data on in trans or in cis observations for this variant was identified. Details ▾Hide ▴

Still missing

No data on observation in trans or in cis with other pathogenic NBN variants

BP5 BP5 requires identification of the variant in a case with an alternate molecular basis for disease. No data was available to assess whether any observed carriers had an alternative genetic diagnosis explaining their phenotype. Details ▾Hide ▴

Still missing

No data on alternate molecular diagnoses in variant carriers

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to same amino acid change as previously established pathogenic missense variant. This is a frameshift deletion, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_002485.4:c.657_661del is a frameshift deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants at the same residue as a known pathogenic missense change. NM_002485.4:c.657_661del is a 5-bp frameshift deletion, not a missense variant, and has no resolvable single amino acid residue for PM5 comparison. Details ▾Hide ▴

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BS2 N/ABS2 applies to observation in healthy adults for a fully penetrant dominant disorder. NBN-related disease is primarily autosomal recessive (Nijmegen breakage syndrome), and the heterozygous cancer risk is incompletely penetrant. The BS2 framework does not cleanly apply. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_002485.4:c.657_661del is itself a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. Computational predictors (REVEL, BayesDel, SpliceAI) are not designed for or applicable to frameshift truncation variants. The variant's impact is through protein truncation, not missense or splicing effects. Details ▾Hide ▴

Evidence considered

SpliceAI delta=0.0 (no splice effect
but this is a frameshift
not a splicing variant)
REVEL and BayesDel not applicable to deletions

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002485.4:c.657_661del is a 5-bp frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: NBN
Transcript: NM_002485.4
Coding (HGVS c.): NM_002485.4:c.657_661del
Protein (HGVS p.): NP_002476.2:p.(Lys219AsnfsTer16)
GRCh38: chr8:89971213 ATTTGT>A
GRCh37: chr8:90983441 ATTTGT>A
ClinVar: 6940
COSMIC: COSV55370851

Gene diagram

Every interpreted variant in NBN, mapped onto the exon structure of NM_002485.4. Select a row to find it on the plot.

NBNNM_002485.4

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 NBN — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 363 / 1,613,090 alleles AF 0.000225 · 0 homozygotes · FAF 0.000265

gnomAD v2.1 57 / 282,132 alleles AF 0.000202 · 0 homozygotes · FAF 0.000297

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00023 · 363 / 1,613,090 alleles · 0 hom · FAF 0.00027

European (non-Finnish)344 / 1,179,482	0.00029
Remaining individuals9 / 62,420	0.00014
European (Finnish)6 / 63,946	9.4e-05
African/African American3 / 74,880	4e-05
Admixed American1 / 59,938	1.7e-05

0 alternate alleles recorded in 5 other groups: Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0002 · 57 / 282,132 alleles · 0 hom · FAF 0.0003

European (non-Finnish)52 / 128,774	0.0004
Remaining individuals1 / 7,190	0.00014
European (Finnish)2 / 25,072	8e-05
African/African American1 / 24,900	4e-05
Admixed American1 / 35,312	2.8e-05

0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000225034; MAF= 0.02250%, 363/1613090 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000291653; MAF= 0.02917%, 344/1179482 alleles, homozygotes = 0); grpmax FAF= 0.00026547.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0003256975355553143, 6/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +101 bp

0.000

SpliceAI acceptor gainat +77 bp

0.000

SpliceAI donor lossat -40 bp

0.000

SpliceAI donor gainat +184 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.0
no predicted splice impact
REVEL/BayesDel not applicable to deletion variants
HCI prior not available for NBN

Sources

spliceai ↗

Evidence considered

SpliceAI delta=0.0 (no splice effect
but this is a frameshift
not a splicing variant)
REVEL and BayesDel not applicable to deletions

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002485.4:c.657_661del is a 5-bp frameshift deletion, 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).

8 paper records listed. 8 cited in the classification.

Cited in the classification

Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group.

The International Nijmegen Breakage Syndrome Study Group evaluated 55 NBS patients from the NBS registry. The majority carried the homozygous 657del5 (657-661delACAAA) truncating mutation in exon 6 of NBS1. Four additional truncating mutations were identified in patients with other haplotypes. No specific genotype-phenotype correlation was found; 40% of patients developed malignancy before age 21.
→ PVS1 → PS4 → PP1 Names this variant
PMID 10799436 ↗
Source detail

Most of them had shown a truncating 5 bp deletion 657–661 delACAAA.

Location Abstract; Results, Table 1 (patient genotypes); Discussion
Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome.

Kleier S et al. · 2000 May

Kleier et al. reported a 5-year-old Bosnian boy with severe microcephaly and chromosomal rearrangements involving chromosomes 7 and 14, initially diagnosed as ataxia telangiectasia. DNA analysis revealed homozygosity for the 657del5 mutation in NBS1 exon 6, confirming the diagnosis of Nijmegen breakage syndrome.
→ PVS1 → PS4 Names this variant
PMID 10852373 ↗
Source detail

This patient is homozygous for the 657del5 mutation.

Location Abstract; Clinical Report; Discussion
Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations.

Varon et al. estimated the prevalence of the 657del5 founder mutation in three Slav populations by screening 4416 Guthrie cards. The carrier frequency was 1/177 overall, with the highest in Czech Republic (1/154). 82 of 84 unrelated NBS patients analyzed were homozygous for 657del5. NBS patients are often diagnosed late, with 14-37% already having malignancy at diagnosis.
→ PVS1 → PS4 Names this variant
PMID 11093281 ↗
Source detail

Most of the NBS patients known so far are of Slav origin and carry a major founder mutation 657del5 in exon 6 of the NBS1 gene.

Location Abstract; Results, Tables 1-2; Discussion
An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.

Maser RS et al. · 2001 Apr

Maser et al. demonstrated that the common NBS1 657del5 allele produces two protein products: a 26-kD N-terminal fragment (NBS1p26) containing FHA/BRCT domains but lacking the MRE11 interaction domain, and a 70-kD protein (NBS1p70) generated by internal translation initiation from cryptic ATG codons brought into frame by the deletion. NBS1p70 retains the MRE11 interaction domain and partially restores nuclear localization of the MRE11 complex but does not confer full function: NBS 657del5 LCLs exhibit radioresistant DNA synthesis. NBS1p70 is detected in lymphoblastoid cells but not fibroblasts.
→ PVS1 → PS3 → PM1 Names this variant
PMID 11279524 ↗
Source detail

NBS1p70 does not confer full function within the MRE11 complex.

Location Abstract; Results para 1-8; Figures 1-4

Context EBV-transformed lymphoblastoid cell lines, untransformed fibroblasts; immunoprecipitation, western blot, in vitro transcription-translation, bicistronic expression constructs
NBS1 is a prostate cancer susceptibility gene.

Cybulski C et al. · 2004 Feb 15

Cybulski et al. studied the 657del5 NBS1 founder allele in prostate cancer. The mutation was present in 5/56 (9%) familial prostate cancer cases (OR=16, P<0.0001), 7/305 (2.2%) nonfamilial cases (OR=3.9, P=0.01), and 9/1500 (0.6%) controls. LOH analysis showed loss of the wild-type NBS1 allele in 7/8 prostate tumors from mutation carriers versus 1/9 from noncarriers (P=0.003). The mutation segregated with prostate cancer in all 4 tested families.
→ PS4 → PP1 Names this variant
PMID 14973119 ↗
Source detail

The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001).

Location Abstract; Results and Discussion; Figures 1-3
The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer.

Dzikiewicz-Krawczyk A · 2008 Sep-Oct

Dzikiewicz-Krawczyk reviewed the role of MRN complex genes in cancer. The 657del5 mutation is discussed as the most common NBS1 mutation, associated primarily with leukemia/lymphoma and breast cancer in heterozygous carriers. The review summarizes that the 657del5 allele produces both a truncated p26 (FHA/BRCT domains) and p70 fragment (MRE11 interaction domain), with p70 levels correlated with cancer occurrence in NBS patients.
→ PM1 Names this variant
PMID 18606567 ↗
Source detail

Heterozygous NBS1 mutations and molecular variants 657del5, I171V, R215W and E185Q were most commonly analyzed. Among these, an association with cancer was found most frequently for 657del5.

Location Section 3, Table 1; Section 2
Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients.

Ciara et al. screened 104 Polish pediatric medulloblastoma patients for NBN mutations and identified 7 heterozygous carriers (6.7%). Three carried c.657_661del5 and four carried c.511A>G. The c.657_661del5 carrier frequency in medulloblastoma was 2.88% versus 0.59% in population controls (OR=4.86, P=0.0028). For classic-type medulloblastoma, the OR was 6.83 (P=0.0001). No LOH was observed in the 5 tested tumors from NBN mutation carriers.
→ PS4 → PP1 Names this variant
PMID 19908051 ↗
Source detail

heterozygous carriers of the germ-line NBN gene mutations (c.511A>G and c.657_661del5) may exhibit increased susceptibility to developing MB.

Location Abstract; Results, Tables 1-4; Discussion
Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

Varon et al. positionally cloned the NBN (NBS1) gene and identified nibrin as a novel DNA double-strand break repair protein. The 657del5 mutation was identified as the major mutation in NBS patients. This is the seminal discovery paper for the NBN gene and the 657del5 founder mutation.
→ PVS1 Names this variant
PMID 9590180 ↗
Source detail

We describe the positional cloning of a gene encoding a novel protein, nibrin, is mutated in Nijmegen breakage syndrome.

Location Abstract (snippet); full text not available

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

gnomAD v4.1 363 / 1,613,090 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 38 Pathogenic · 1 risk factor 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

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0003256975355553143, 6/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Pathogenic (38 clinical laboratories) and as risk factor (1 clinical laboratory). (ClinVarID = 6940)

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 previously been reported in somatic cancers (COSMIC; COSV55370851, n = 6 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.