8-89971173-CTGTT-C

Position:

• chr8-89971173-CTGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002485.5(NBN):​c.698_701delAACA​(p.Lys233fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,611,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NBN NM_002485.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 7.59

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-89971173-CTGTT-C is Pathogenic according to our data. Variant chr8-89971173-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 127878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89971173-CTGTT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.698_701delAACA	p.Lys233fs	frameshift_variant, splice_region_variant	6/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.698_701delAACA	p.Lys233fs	frameshift_variant, splice_region_variant	6/16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250094 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135224

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1459500 Hom.: 0 AF XY: 0.000105 AC XY: 76 AN XY: 726074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2018	Variant summary: NBN c.698_701delAACA (p.Lys233SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 252006 control chromosomes (gnomAD). The variant, c.698_701delAACA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and Nijmegen Breakage Syndrome (Varon_1998, Gass_2017, Ramus_2015, Li_2015, Susswein_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Lys233Serfs*5) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs587780100, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (NBS), and breast/ovarian cancer (PMID: 9590180, 15474156, 26315354, 26534844). This variant is also known as 698del4. ClinVar contains an entry for this variant (Variation ID: 127878). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 02, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NBN: PVS1, PS4:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as NBS1 698del4; This variant is associated with the following publications: (PMID: 9590180, 26681312, 24072268, 29915322, 31948886, 26315354, 26534844, 23149842, 27038244, 28374160, 28152038, 30043523, 29961768, 29625052, 26689913, 35626031, 34326862, 33804961, 32427313, 29922827, 32885271, 32338768, 28888541, 36451132, 36623239, 15474156) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2024	The NBN c.698_701del (p.Lys233Serfs*5) variant alters the translational reading frame of the NBN mRNA and causes the premature termination of NBN protein synthesis. This variant has been reported in the published literature in reported in the biallelic state in multiple individuals with Nijmegen breakage syndrome (PMID 9590180 (1998), 10799436 (2000), 15474156 (2004)), as well as in the heterozygous state in multiple individuals with prostate cancer (PMID: 29915322 (2018)), pancreatic cancer (PMID: 29961768 (2019)), lung cancer (PMID: 26681312 (2015)), ovarian cancer (PMID: 26315354 (2015), PMID: 28888541 (2017)), and breast cancer and skin cancers (PMID: 28374160 (2017), 30043523 (2018)). The frequency of this variant in the general population, 0.000065 (2/30740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 07, 2022

- -

Aplastic anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

NBN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The NBN c.698_701delAACA variant is predicted to result in a frameshift and premature protein termination (p.Lys233Serfs*5). This variant has been reported in a patient with Nijmemgen breakage syndrome (Varon et al. 1998. PubMed ID: 9590180) and in individuals with various cancers, including breast and skin, prostate, or ovarian cancers (for example, Gass et al. 2017. PubMed ID: 28374160; Supplementary Table, Lerner-Ellis. 2020. PubMed ID: 32885271; Table S7, Lilyquist. 2017. PubMed ID: 28888541). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and has been interpreted as pathogenic in ClinVar. Frameshift variants in NBN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The NBN p.Lys233SerfsX5 variant was identified in 2 of 7792 proband chromosomes (frequency: 0.00026) from individuals or families with hereditary breast and ovarian cancer (Li_2015, Ramus_2015). The variant was also identified in dbSNP (ID: rs587780100) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx, Ambry Genetics, University of Chicago, Invitae, Color Genomics, OMIM and GeneReviews), Clinvitae (3x as in ClinVar), LOVD 3.0, and Zhejiang Colon Cancer Database. The variant was not identified in Cosmic database. The variant was identified in control databases in 5 of 245144 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15226 chromosomes (freq: 0.000066), European (Non-Finnish) in 4 of 111062 chromosomes (freq: 0.000036), but it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The variant has been reported in families with Nijmegen Breakage Syndrome as well as in individuals with hereditary breast and ovarian cancer (HBOC), and is reported as a variant of English origin (Cybulski_2013, Meyer_2004, Varon_1998). The p.Lys233SerfsX5 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 233 and leads to a premature stop codon at position 237. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the NBN gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The c.698_701delAACA pathogenic mutation, located in coding exon 6 of the NBN gene, results from a deletion of 4 nucleotides at nucleotide positions 698 to 701, causing a translational frameshift with a predicted alternate stop codon (p.K233Sfs*5). This alteration was detected in a series of individuals with Nijmegen breakage syndrome (NBS) (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in a woman with bilateral breast cancer, multiple skin cancers, and a family history of cancer and a male patient with prostate cancer (Gass J et al. Fam. Cancer. 2017 Oct;16:551-553; Wu Y et al. Eur Urol Oncol. 2020 Apr;3(2):224-230). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780100; hg19: chr8-90983401;