NBN

Final classification

VUS

NBN c.1873G>T · p.Glu625Ter

NBN

Gene

NBN

Transcript

NM_002485.4

HGVS · transcript:coding

NM_002485.4:c.1873G>T

Consequence

N/A

GRCh38

chr8:89947865 C>A

GRCh37

chr8:90960093 C>A

Basis 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. ▾

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.

Classification rationale

PVS1PM2 VUS

NBN c.1873G>T

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.¹ 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.² 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.³ 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.⁴

PVS1 + PM2 → VUS

1 pvs1_variant_assessment

2 PMID:9590180 ↗pvs1_gene_context

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 pvs1_generic_framework ↗generic_acmg_combination_rules

Gene diagram · NM_002485.4 · variants mapped to exon structure

NBN NM_002485.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

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.

Nonsense variant p.Glu625Ter in exon 12/16NMD predictedNBN loss of function is established germline disease mechanism (Nijmegen breakage syndrome

pvs1_generic_framework ↗PMID:9590180 ↗gnomad_v4 ↗

✓

PM2 supporting Pathogenic

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%.

gnomAD v2.1: absentgnomAD v4.1: 0/1578

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No de novo data is available for this variant in any publication or database.

PS3 No functional data exists for NM_002485.4:c.1873G>T in the literature.

PS4 No case-control or prevalence data comparing this variant in affected versus unaffected individuals is available.

PM1 The variant creates a premature stop codon at position 625.

PM6 No de novo observation has been reported for this variant in any publication or database.

PP1 No segregation data is available for this variant in affected families.

PP3 In silico predictors are not informative for nonsense variants: BayesDel (0.65) and REVEL (not found) are designed for missense substitutions.

PP4 No patient phenotype or clinical data is available for this variant.

PP5 This variant is absent from ClinVar.

Benign

BA1 The variant is absent from gnomAD (0/1,578,428 alleles).

BS1 The variant is absent from gnomAD (0/1,578,428 alleles).

BS2 No observation of this variant in healthy adults has been reported.

BS3 No functional data demonstrating a benign or neutral effect exists for this variant.

BS4 No segregation data demonstrating lack of cosegregation with disease is available.

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.

BP4 Multiple lines of computational evidence do not suggest a benign impact.

BP5 No evidence is available demonstrating that the variant is found in a case with an alternate molecular basis for disease.

BP6 The variant is absent from ClinVar.

N/A · 6 PS1 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,578,428
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

PMID 9590180 ↗ ONCOKB · functional

Searched

c.1873G>TE625*Glu625TerE625X1873

Found

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.

Variant

◇ Residue / gene-level — variant not named

Applied to

→PVS1 supports · met

Why

Variant not identified in this paper. Cited for PVS1 at the gene level: this paper establishes that biallelic truncating NBN mutations cause Nijmegen breakage syndrome, confirming loss of function as the disease mechanism.

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 · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots