0%
NBNc.1873G>TUncertain significance
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Variant interpretation report

NBN c.1873G>T, p.(Glu625Ter)

NM_002485.4:c.1873G>T NP_002476.2:p.(Glu625Ter) View identifiers
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.

About NBN

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

This variant is a nonsense change (NP_002476.2:p.Glu625Ter) in exon 12 of 16, predicted to trigger nonsense-mediated decay. NBN loss of function is an established disease mechanism for Nijmegen breakage syndrome, an autosomal recessive chromosomal instability disorder. Under the ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 at very strong strength applies to null variants in genes where LOF is a known disease mechanism.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and v4.1 (0/1,578,428 alleles across all populations). Under generic ACMG/AMP criteria, absence from population databases supports pathogenicity at the supporting level when allele frequency is below 0.1%.

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 very strong, PM2 supporting; combination = 1 very 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.

SpliceAI score
0.380 maximum delta

Recorded SpliceAI maximum delta score: 0.380. 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

27 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002485.4:c.1873G>T (p.Glu625Ter) is a nonsense variant in exon 12 of the NBN gene, predicted to introduce a premature termination codon at position 625 of 755 amino acids and trigger nonsense-mediated decay.

NBN encodes nibrin, a component of the MRE11-RAD50-NBN (MRN) complex critical for DNA double-strand break repair. Biallelic loss-of-function variants in NBN cause Nijmegen breakage syndrome, an autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiation sensitivity, and cancer predisposition (PMID:9590180). Loss of function is the established disease mechanism.

This variant is absent from gnomAD v2.1 and v4.1 (0/1,578,428 alleles across all populations), consistent with a rare disease-causing allele.

Under the generic ACMG/AMP 2015 framework, this variant meets PVS1 at very strong strength (null variant in a gene where LOF is a known disease mechanism, NMD predicted) and PM2 at supporting strength (absent from population databases). No benign criteria were met.

Met · 2

PVS1 Very strongThis variant is a nonsense change (NP_002476.2:p.Glu625Ter) in exon 12 of 16, predicted to trigger nonsense-mediated decay. NBN loss of function is an established disease mechanism for Nijmegen breakage syndrome, an autosomal recessive chromosomal instability disorder. Under the ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 at very strong strength applies to null variants in genes where LOF is a known disease mechanism. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Glu625Ter in exon 12/16
  • NMD predicted
  • NBN loss of function is established germline disease mechanism (Nijmegen breakage syndrome
  • autosomal recessive)
  • Original NBS1 gene cloning paper (PMID:9590180) demonstrates that biallelic truncating NBN mutations cause Nijmegen breakage syndrome
  • Transcript NM_002485.4 is the RefSeq select transcript for NBN
  • Variant is absent from gnomAD
  • consistent with a disease-causing null allele
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:9590180 ↗gnomad_v4 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and v4.1 (0/1,578,428 alleles across all populations). Under generic ACMG/AMP criteria, absence from population databases supports pathogenicity at the supporting level when allele frequency is below 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 0/1
  • 578
  • 428 alleles (AF = 0.00000)
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo data is available for this variant in any publication or database. Details ▾Hide ▴
Still missing
  • No de novo observation reported
PS3 No functional data exists for NM_002485.4:c.1873G>T in the literature. The sole paper retrieved (PMID:9590180) describes the original cloning of NBS1 and characterization of six truncating mutations in Nijmegen breakage syndrome patients, but c.1873G>T / p.Glu625Ter is not among them. OncoKB annotates this variant as Likely Loss-of-function and Likely Oncogenic, but this represents curated inference from gene-level knowledge rather than variant-specific experimental functional data. Details ▾Hide ▴
Evidence considered
  • OncoKB classifies as Likely Loss-of-function / Likely Oncogenic — curated annotation only
  • PMID:9590180 does not contain the variant
  • no variant-specific functional assay was performed
Still missing
  • No variant-specific functional assay data available
Sources
oncokb ↗PMID:9590180 ↗
PS4 No case-control or prevalence data comparing this variant in affected versus unaffected individuals is available. Details ▾Hide ▴
Still missing
  • No case-control or cohort data for this variant
PM1 The variant creates a premature stop codon at position 625. The N-terminal FHA domain (residues 24-100) and BRCT domain (residues 105-190) — the two recognized functional domains in nibrin — remain intact upstream of the truncation. The cancerhotspots.org residue-level analysis does not identify codon 625 as a statistically significant hotspot. The truncation removes the C-terminal region involved in MRE11 interaction, but this is not a discrete characterized domain; the loss-of-function effect is already captured by PVS1. Details ▾Hide ▴
Evidence considered
  • FHA (24-100) and BRCT (105-190) domains remain intact upstream of truncation
  • Cancerhotspots.org: residue 625 is not a statistically significant hotspot
  • Truncation removes C-terminal MRE11-interacting region but no discrete functional domain is defined at this position
Sources
PMID:9590180 ↗
PM6 No de novo observation has been reported for this variant in any publication or database. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No segregation data is available for this variant in affected families. Details ▾Hide ▴
Still missing
  • No familial segregation data available
PP3 In silico predictors are not informative for nonsense variants: BayesDel (0.65) and REVEL (not found) are designed for missense substitutions. SpliceAI shows a modest delta score of 0.38 (donor loss 0.38, acceptor loss 0.31), which is borderline and does not reach the 0.5 threshold for confident splice prediction. Furthermore, the loss-of-function effect is already captured by PVS1 at very strong strength; applying PP3 for the same underlying mechanism would constitute double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.38 (donor loss 0.38
  • acceptor loss 0.31) — borderline
  • below 0.5 threshold
  • BayesDel = 0.65 — designed for missense variants
  • not informative for nonsense
  • REVEL not available
  • HCI prior not available
  • PVS1 already captures the LOF effect
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or clinical data is available for this variant. The variant is absent from ClinVar and no case reports describe its clinical presentation. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no patient phenotype data available
Still missing
  • No patient clinical data or phenotype specificity information
Sources
clinvar ↗
PP5 This variant is absent from ClinVar. PP5 requires a reputable source (e.g., ClinVar 3-star expert panel) classifying the variant as pathogenic. No such classification exists. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no expert panel classification available
Still missing
  • No ClinVar expert panel classification
Sources
clinvar ↗
BA1 The variant is absent from gnomAD (0/1,578,428 alleles). BA1 requires an allele frequency above 1% in population databases. The observed frequency of 0% does not support a benign classification. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00000 (0/1
  • 578
  • 428 alleles)
  • Allele frequency is well below the 1% BA1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD (0/1,578,428 alleles). BS1 requires an allele frequency above 0.3%. The observed frequency of 0% does not support a likely benign threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00000 (0/1
  • 578
  • 428 alleles)
  • Allele frequency is well below the 0.3% BS1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in healthy adults has been reported. The variant is absent from gnomAD and has no clinical observations. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • no healthy adult carriers identified
Still missing
  • No observation in healthy adult controls
Sources
gnomad_v4 ↗
BS3 No functional data demonstrating a benign or neutral effect exists for this variant. OncoKB classifies the variant as Likely Loss-of-function, which is consistent with a deleterious effect, not a benign one. Details ▾Hide ▴
Evidence considered
  • No functional studies showing normal protein function
  • OncoKB annotation suggests loss-of-function
  • not benign effect
Still missing
  • No functional data demonstrating benign effect
Sources
oncokb ↗
BS4 No segregation data demonstrating lack of cosegregation with disease is available. Details ▾Hide ▴
Still missing
  • No segregation data for benign assessment
BP2 No data is available regarding whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
  • No trans/cis phase data available
BP4 Multiple lines of computational evidence do not suggest a benign impact. SpliceAI predicts a modest splice-altering effect (max delta 0.38), and BayesDel (0.65) is in the pathogenic range. REVEL is unavailable. The collective computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.38 — suggests possible splice impact
  • not consistent with benign
  • BayesDel = 0.65 — above pathogenic threshold
  • inconsistent with BP4
  • REVEL not available
Sources
spliceai ↗bayesdel
BP5 No evidence is available demonstrating that the variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnosis
BP6 The variant is absent from ClinVar. BP6 requires a reputable source reporting the variant as benign. No such source exists. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification available
Still missing
  • No ClinVar or expert panel benign classification
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the variant causes the same amino acid change as a known pathogenic variant via a different nucleotide change. This is a nonsense variant creating a premature stop codon; no same-amino-acid-change comparator exists. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants at the same codon as a known pathogenic missense change. This is a nonsense variant; the PM5 candidate search confirmed no same-residue comparators are applicable. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change; PP2 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. This variant is itself a truncating (nonsense) variant, so BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in non-repeat regions. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) change, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies when a different nucleotide change at the same position has been independently reported as pathogenic in a reputable source. This is a nonsense variant; PS5 is designed for alternate pathogenic nucleotide changes producing the same missense substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
NBN
Transcript
NM_002485.4
Coding (HGVS c.)
NM_002485.4:c.1873G>T
Protein (HGVS p.)
NP_002476.2:p.(Glu625Ter)
GRCh38
chr8:89947865 C>A
GRCh37
chr8:90960093 C>A

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…
gnomAD v4.1 0 / 1,578,428 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,578,428 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1578428 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74118 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +27 bp
0.310
SpliceAI acceptor gainat +221 bp
0.000
SpliceAI donor lossat -41 bp
0.380
SpliceAI donor gainat +52 bp
0.000
Pangolin splice lossmagnitude shown
-0.460
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.650

How the predictions were used

PP3 In silico predictors are not informative for nonsense variants: BayesDel (0.65) and REVEL (not found) are designed for missense substitutions. SpliceAI shows a modest delta score of 0.38 (donor loss 0.38, acceptor loss 0.31), which is borderline and does not reach the 0.5 threshold for confident splice prediction. Furthermore, the loss-of-function effect is already captured by PVS1 at very strong strength; applying PP3 for the same underlying mechanism would constitute double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.38 (donor loss 0.38
  • acceptor loss 0.31) — borderline
  • below 0.5 threshold
  • BayesDel = 0.65 — designed for missense variants
  • not informative for nonsense
  • REVEL not available
  • HCI prior not available
  • PVS1 already captures the LOF effect
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not suggest a benign impact. SpliceAI predicts a modest splice-altering effect (max delta 0.38), and BayesDel (0.65) is in the pathogenic range. REVEL is unavailable. The collective computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.38 — suggests possible splice impact
  • not consistent with benign
  • BayesDel = 0.65 — above pathogenic threshold
  • inconsistent with BP4
  • REVEL not available
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) change, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.38). BayesDel score = 0.65.

1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.
    Varon et al. (1998) report the positional cloning of NBS1 and identification of six truncating mutations (657del5, 698del4, 835del4, 842insT, 1142delC, 976C>T) in Nijmegen breakage syndrome patients. NM_002485.4:c.1873G>T (p.Glu625Ter) was not among the mutations identified in this study.
    → PVS1 Does not name this variant
    PMID 9590180 ↗
    Source detail
    Mutation screening of the NBS1 gene identified a total of six distinct mutations in various NBS patients, summarized in Table 1.

    Location Table 1 lists all six mutations identified; c.1873G>T is not present in the mutation table or anywhere in the full text

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

gnomAD v4.1 0 / 1,578,428 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.380 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

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= 0; MAF= 0.00000%, 0/1578428 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74118 alleles, homozygotes = 0).

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 possible splice impact for this variant (max delta score = 0.38). BayesDel score = 0.65.

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.