NM_002485.4:c.1873G>T

NBN · NP_002476.2:p.(Glu625Ter) · NM_002485.4

GRCh37: chr8:90960093 C>A · GRCh38: chr8:89947865 C>A

Gene: NBN Transcript: NM_002485.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

NBN

Transcript

NM_002485.4

Protein

NP_002476.2:p.(Glu625Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:9590180 gnomad_v4
PS1	N/A	PS1 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.
PS2	Not met	No de novo data is available for this variant in any publication or database.
PS3	Not met	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.	oncokb PMID:9590180
PS4	Not met	No case-control or prevalence data comparing this variant in affected versus unaffected individuals is available.
PS5	N/A	PS5 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.
PM1	Not met	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.	PMID:9590180
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant in any publication or database.
PP1	Not met	No segregation data is available for this variant in affected families.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change; PP2 is not applicable.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	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.	clinvar
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in healthy adults has been reported. The variant is absent from gnomAD and has no clinical observations.	gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease is available.
BP1	N/A	BP1 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.
BP2	Not met	No data is available regarding whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in non-repeat regions. This variant is a single-nucleotide substitution, not an in-frame indel.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	No evidence is available demonstrating that the variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	The variant is absent from ClinVar. BP6 requires a reputable source reporting the variant as benign. No such source exists.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) change, not a synonymous variant.

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