Variant classification summary

NM_002485.4:c.657_661del

NBN · NP_002476.2:p.(Lys219AsnfsTer16) · NM_002485.4

GRCh37: chr8:90983441 ATTTGT>A · GRCh38: chr8:89971213 ATTTGT>A

Gene: NBN Transcript: NM_002485.4

Final call

Pathogenic

PVS1 very strong PS3 moderate PS4 strong PM1 supporting PM2 supporting PP1 moderate PP5 supporting

Variant details

Gene

NBN

Transcript

NM_002485.4

Protein

NP_002476.2:p.(Lys219AsnfsTer16)

gnomAD AF

0.00022503394106962414 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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).

4

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.

5

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.

6

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.

7

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

8

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:11279524 PMID:10799436 PMID:11093281
PS1	N/A	PS1 applies to same amino acid change as previously established pathogenic missense variant. This is a frameshift deletion, not a missense change.
PS2	Not met	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.
PS3	Met	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.	PMID:11279524
PS4	Met	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.	PMID:10799436 PMID:11093281 PMID:14973119 PMID:19908051 gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not met	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.
PM1	Met	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.	PMID:11279524 PMID:18606567
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 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.
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	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.
PP1	Met	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.	PMID:10799436 PMID:14973119 PMID:19908051
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not assessed	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.
PP5	Met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	N/A	BS2 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.
BS3	Not met	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.	PMID:11279524
BS4	Not met	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).	PMID:10799436 PMID:14973119 PMID:19908051
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_002485.4:c.657_661del is itself a truncating (frameshift) variant.
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame change.
BP4	N/A	BP4 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.	spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

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