chr8-89971213-ATTTGT-A

Variant names:

• chr8-89971213-ATTTGT-A
• rs587776650
• NM_002485.5:c.657_661delACAAA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PP5_Strong

The NM_002485.5(NBN):c.657_661delACAAA (p.Lys219AsnfsTer16) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.000225 (AC=363) in the gnomAD database across 1,613,090 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00028. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000218835: Experimental studies have shown that this premature translational stop signal affects NBN function (PMID:16033915, 22131123, 22941933)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: NBN NM_002485.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:47 U:1 O:4
• Conservation: PhyloP100: 2.47
• Publications: 1 publications found

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Orphanet, G2P, Myriad Women's Health, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: Natera
• hereditary breast carcinoma

  Inheritance: Unknown, AD Classification: NO_KNOWN Submitted by: Natera, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 6 of 16) at amino acid 219 of 754, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~233 amino acids (521 amino acids lost).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000218835: Experimental studies have shown that this premature translational stop signal affects NBN function (PMID: 16033915, 22131123, 22941933).; SCV001365920: "In vitro functional studies support an impact on protein function and show that this variant leads to the production of an abnormal protein product." (Maser 2001, Dzikiewicz-Krawczyk 2012); SCV000183792: "However, functional studies have indicated that this alteration may partially escape nonsense-mediated decay and produce a protein with some residual function (Maser RS et al. Nat Genet, 2001 Apr;27:417-21)."; SCV000821748: Experimental studies propose that this deletion encodes a partially functional protein that diminishes the severity of the NBS phenotype (PMID: 11279524).; SCV000889554: Functional studies have shown that this variant results in two proteins, the N-terminal p26 fragment and the p70 fragment produced from an internal initiation codon at position p.221 that lacks the N-terminal portion (PMID: 11279524 (2001), 25485873 (2014)). Another study has shown that the variant caused increased chromosomal instability in homozygous cells (PMID: 22131123 (2012)).; SCV001160103: However, functional studies show two in-frame start codons created by the frameshift that can generate truncated NBN proteins with partial functionality (Lins 2009, Maser 2001).; SCV001553205: Functional studies have reported that the variant leads to two truncated fragments, p26 and p70 nibrin, and the translation of a short N-terminal protein with FHA/BRCT domains, therefore maintaining some function of the full-length NBS1 protein (Dzikiewicz-Krawczyk 2008, Cilli 2014).; SCV000806448: Functionally, it has been hypothesized to be a hypomorph, which results in a truncated protein with residual activity of the full-length NBN protein (Maser et al. 2001. PubMed ID: 11279524; Dzikiewicz-Krawczyk et al. 2011. PubMed ID: 22131123).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (47/48 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NBN NM_002485.5	MANE Select	c.657_661delACAAA p.Lys219AsnfsTer16	frameshift	Exon 6 of 16	Prot: NP_002476.2
	NBN NM_001024688.3		c.411_415delACAAA p.Lys137AsnfsTer16	frameshift	Exon 7 of 17	Prot: NP_001019859.1 UniProt:
	NBN NM_001440379.1		c.411_415delACAAA p.Lys137AsnfsTer16	frameshift	Exon 6 of 16	Prot: NP_001427308.1 UniProt:

NBN NM_002485.5

MANE Select

HGVSc / HGVSpc.657_661delACAAAp.Lys219AsnfsTer16

Exon rankExon 6 of 16

frameshift

Prot: NP_002476.2

NBN NM_001024688.3

HGVSc / HGVSpc.411_415delACAAAp.Lys137AsnfsTer16

Exon rankExon 7 of 17

frameshift

Prot: NP_001019859.1UniProt: A0A0C4DG07

NBN NM_001440379.1

HGVSc / HGVSpc.411_415delACAAAp.Lys137AsnfsTer16

Exon rankExon 6 of 16

frameshift

Prot: NP_001427308.1UniProt: A0A0C4DG07

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NBN ENST00000265433.8	TSL:1MANE Select	c.657_661delACAAA p.Lys219AsnfsTer16	frameshift	Exon 6 of 16	Prot: ENSP00000265433.4 UniProt:
	NBN ENST00000697309.1		c.657_661delACAAA p.Lys219AsnfsTer16	frameshift	Exon 6 of 15	Prot: ENSP00000513244.1 UniProt:
	NBN ENST00000697293.1		c.657_661delACAAA p.Lys219AsnfsTer16	frameshift	Exon 6 of 17	Prot: ENSP00000513230.1 UniProt:

NBN ENST00000265433.8

TSL:1MANE Select

HGVSc / HGVSpc.657_661delACAAAp.Lys219AsnfsTer16

Exon rankExon 6 of 16

frameshift

Prot: ENSP00000265433.4UniProt: O60934

NBN ENST00000697309.1

HGVSc / HGVSpc.657_661delACAAAp.Lys219AsnfsTer16

Exon rankExon 6 of 15

frameshift

Prot: ENSP00000513244.1UniProt: A0A8V8TKY5

NBN ENST00000697293.1

HGVSc / HGVSpc.657_661delACAAAp.Lys219AsnfsTer16

Exon rankExon 6 of 17

frameshift

Prot: ENSP00000513230.1UniProt: A0A8V8TM80

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000197	AC:30	Hom:0	AN:152184	Cov:32
GnomAD2 exomes	AF: 0.000191	AC:48	Hom:	AN:250742	Cov:
GnomAD4 exome	AF: 0.000228	AC:333	Hom:0	AN:1460906	Cov:
GnomAD4 genome	AF: 0.000197	AC:30	Hom:0	AN:152184	Cov:32
TOPMed (Bravo)	AF: 0.000219	AC:58	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000561	AC:17	Hom:0	AN:30298	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
Turkish Variome	AF: 0.000448	AC:3	Hom:0	AN:6690	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000211	6	28414	0.000208	6	28842
Epi25(Epilepsy)	0.000382	16	41924	0.000389	26	66770
SCHEMA(Schizophrenia)	0.000107	13	121644	0.000142	27	190524

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
21	-	-	Microcephaly, normal intelligence and immunodeficiency (22)
9	-	-	not provided (10)
5	1	-	Hereditary cancer-predisposing syndrome (6)
1	-	-	Aplastic anemia (1)
1	-	-	Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
1	-	-	Carcinoma of pancreas (1)
1	-	-	Familial prostate cancer (1)
1	-	-	Hepatocellular carcinoma (1)
1	-	-	Lissencephaly;C4551563:Microcephaly (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	NBN-related disorder (1)
1	-	-	Paediatric disorders (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	3/197	disease causing (fs/PTC)
PhyloP100	Benign	2.5

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs587776650;

hg19: chr8-90983441;

COSMIC: COSV55370851;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar