Variant classification summary

NM_002485.5:c.657_661del

NBN · NP_002476.2:p.(Lys219AsnfsTer16) · NM_002485.5

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

Gene: NBN Transcript: NM_002485.5

Final call

Pathogenic

PVS1 very strong PS3 moderate PS4 strong PM3 moderate

Variant details

Gene

NBN

Transcript

NM_002485.5

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

Pathogenic: PVS1 very strong is met for the early NBN loss-of-function frameshift p.(Lys219AsnfsTer16).

2

Pathogenic: PS3 moderate is met because variant-specific assays showed abnormal NBS1 products and incomplete MRE11-complex function.

3

Pathogenic: PS4 strong is met because familial prostate-cancer cases had OR 16 with a 95% CI excluding 1.

4

Pathogenic: PM3 moderate is met because affected individuals were homozygous or compound heterozygous for c.657_661del.

Final determination: Under the generic ACMG/AMP 2015 rules, one very strong criterion plus one strong criterion supports Pathogenic; PVS1 very strong and PS4 strong satisfy this rule, with PS3 and PM3 adding moderate pathogenic evidence.

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	Met, very strong: exon 6 frameshift p.(Lys219AsnfsTer16) causes an early truncation in NBN, whose loss of function is an established disease mechanism.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:9590180 PMID:10799436 PMID:11279524
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no case-specific confirmed maternity-and-paternity testing demonstrates that this NBN variant arose de novo in the proband.	PMID:16033915 PMID:9590180
PS3	Met	Met at moderate strength: exact 657del5 produced truncated p26 lacking the MRE11-interaction domain and an incomplete p70 product in variant cell assays.	PMID:11279524
PS4	Met	Met: familial prostate-cancer cases had OR 16 versus controls, and 16 > 5.0 with a 95% CI of 5.2-50 excluding 1.	PMID:14973119
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00026547, exceeding the PM2 supporting threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Met	Met: affected NBS individuals were homozygous or compound heterozygous for c.657_661del, supporting occurrence on both disease alleles in this recessive disorder.	PMID:10852373 PMID:9590180 PMID:16033915
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: the available reports show inherited or biallelic NBN genotypes, not a case-specific assumed de novo variant without parental confirmation.	PMID:16033915 PMID:9590180
PP1	Not assessed	Not assessed: no qualifying multiple-affected-member family shows cosegregation of this NBN variant with the relevant disease phenotype.	PMID:9590180 PMID:16033915 PMID:14973119
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the c.657_661del frameshift is outside PP3's missense or splice-region/intronic computational-evidence scope.
PP4	Not assessed	Not assessed: no case-specific phenotype or family-history description is available to establish a highly specific NBN disease presentation.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic submission; available assertions are non-expert submissions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00026547 (0.026547%), far below the BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 clinvar PMID:9590180 PMID:14973119
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00026547 (0.026547%), below the generic BS1 default threshold of 0.01.	gnomad_v4 gnomad_v2 PMID:10799436
BS2	Not met	Not met: no healthy homozygotes were observed, with 0 homozygotes in gnomAD v4.1 across 1,613,090 alleles.	gnomad_v4 gnomad_v2 PMID:10852373
BS3	Not assessed	Not assessed: the only BS3 lead is an unavailable heterozygous-cell summary, insufficient to establish no damaging effect on NBN function or splicing.
BS4	Not assessed	Not assessed: no affected relatives are documented to lack the NBN variant, and normal controls or unaffected parents do not establish affected-family non-segregation.	PMID:9590180 PMID:16033915
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no evidence establishes c.657_661del in cis with a pathogenic variant, and the available NBN disorder evidence is recessive.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the c.657_661del frameshift remains protein-truncating despite SpliceAI max delta 0.001, so BP4 cannot assess no gene-product impact.
BP5	Not assessed	Not assessed: no alternate molecular diagnosis is documented for the case in which this variant was found.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign submission to satisfy the BP6 requirement.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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