rs587776650

chr8-89971213-ATTTGT-A

Variant summary

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

The NM_002485.5(NBN):c.657_661del(p.Lys219AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K219K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• 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:39 U:1 O:4
• Conservation: PhyloP100: 2.47

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]

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 8-89971213-ATTTGT-A is Pathogenic according to our data. Variant chr8-89971213-ATTTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 6940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89971213-ATTTGT-A is described in Lovd as [Pathogenic]. Variant chr8-89971213-ATTTGT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.657_661del	p.Lys219AsnfsTer16	frameshift_variant	6/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.657_661del	p.Lys219AsnfsTer16	frameshift_variant	6/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250742 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1460906 Hom.: 0 AF XY: 0.000239 AC XY: 174 AN XY: 726760

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74346

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.000219

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:39 Uncertain:1 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:19 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 05, 2023	Criteria applied: PVS1,PS3,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 28, 2022	The NBN c.657_661del (p.Lys219fs) change deletes five nucleotides and causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This is the most common pathogenic variant reported in individuals affected with Nijmegen breakage syndrome (PMID: 9590180, 20301355). In addition, this variant has been identified as heterozygous in individuals with many cancer types including breast, lymphoma, prostate, melanoma, medulloblastoma, and others (PMID: 15185344, 14973119, 18606567, 19908051, 24113799). Case-control studies have demonstrated evidence of association with breast cancer (OR = 2.63), prostate cancer (OR = 5.87), and lymphoma (OR = 2.93) (PMID: 23317186, 24113799). This variant is present 5x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 27, 2022	PVS1, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2019	The p.Lys219AsnfsX16 variant in NBN is the most common NBN variant associated with autosomal recessive Nijmegen Breakage Syndrome (NBS) and has been reported as a founder variant in Slavic populations (Varon 1998). Additionally, in the heterozygous state, this variant has been found to increase risk to certain NBS-related cancers (Gao 2013, Zhang 2012). It has also been identified in 52/128774 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 6940). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 219 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NBN gene is an established disease mechanism in autosomal recessive NBS. 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive NBS. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2015	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Lys219Asnfs*16) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 536 amino acid(s) of the NBN protein. This variant is present in population databases (rs587776650, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with NBN-related conditions (PMID: 14973119, 15185344, 18606567, 19908051, 24113799). It is commonly reported in individuals of Slavic ancestry (PMID: 9590180). This variant is also known as 657del5. ClinVar contains an entry for this variant (Variation ID: 6940). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NBN function (PMID: 16033915, 22131123, 22941933). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2008	- -
Pathogenic, criteria provided, single submitter	research	Miami Human Genetics, University Of Miami Miller School Of Medicine	Nov 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). It is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006940 / PMID: 9590180). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 12, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:6 Other:1

risk factor, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2019	The p.Lys219AsnfsX16 variant in NBN is associated with an increased risk for NBN-related cancers (Gao 2013, Zhang 2012). Large meta-analyses have reported significant odds ratios in carriers of the variant for multiple cancers, particularly breast cancer (OR = 2.63 [95% CI=1.76-3.93]), prostate cancer (OR = 5.87 [95% CI=2.51-13.75]), and lymphoma (OR = 2.93 [95% CI=1.62-5.29]) (Gao 2013, Zhang 2012). Additionally, in the bi-allelic state, this variant is the most common variant associated with autosomal recessive Nijmegen Breakage Syndrome (NBS). It has also been identified in 52/128774 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 6940). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 219 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NBN gene is an established disease mechanism in autosomal recessive NBS. 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). In summary, this variant meets criteria to be classified as an established risk allele for breast, prostate, and lymphoid cancers. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	The NBN c.657_661del; p.Lys219AsnfsTer16 variant (rs587776650), also known as 657del5, is reported in the literature as the most common pathogenic variant and a founder mutation in the Slavic population in individuals affected with Nijmegen breakage syndrome (Varon 1998). Heterozygous carriers are also reported to have an increased risk for various cancers, including breast cancer, prostate cancer, colorectal cancer, lymphoma, melanoma, and medulloblastoma (Ciara 2010, Gao 2013, Steffen 2004). However, more recent large, multi-ethnic case control studies have demonstrated that heterozygous pathogenic NBN variants are not associated with an increased risk for breast cancer (Breast Cancer Association Consortium 2021, Hu 2021). Data regarding other cancer risks remains inconclusive. This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6940), and is found in the non-Finnish European population with an allele frequency of 0.040% (52/128,774 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. 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). Based on available information, the p.Lys219AsnfsTer16 variant is considered to be pathogenic. References: Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021;384(5):428-439. PMID: 33471991 Ciara E et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010 Mar;119(3):325-34. PMID: 19908051. Gao P et al. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis. 2013 Nov;28(6):683-97. PMID: 24113799. Hu C et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021;384(5):440-451. PMID: 33471974 Lins S et al. Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. Gene. 2009 Nov 1;447(1):12-7. PMID: 19635536. Maser RS et al. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet. 2001 Apr;27(4):417-21. PMID: 11279524. Steffen J et al. Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer. 2004 Aug 10;111(1):67-71. PMID: 15185344. Varon R et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998 May 1;93(3):467-76. PMID: 9590180. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NBN: PVS1, PS3, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 22, 2022	This frameshift variant alters the translational reading frame of the NBN mRNA and causes the premature termination of NBN protein synthesis. 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)). The frequency of this variant in the general population, 0.00041 (21/50678 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. The c.657_661del variant is the most common pathogenic variant found in individuals affected by Nijmegen breakage syndrome (NBS) (PMID: 9590180 (1998), 20301355 (2017)). In the published literature, previous studies showed an association to breast cancer (PMID: 12845677 (2003), 22491912 (2012), 23317186 (2012)), however, recent studies do not support this association (PMID: 34072463 (2021), 33471974 (2021), 33471991 (2021)). The variant is also reported to have an increased risk overall for cancer (PMID: 24113799 (2013), 15185344 (2004)), including pancreatic cancer (PMID: 27150568 (2016), 35309086 (2022)), prostate cancer (PMID: 14973119 (2004)), medulloblastoma (PMID: 19908051 (2010)), and relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (PMID: 29419426 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2021	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; Case control studies suggest this variant is associated with prostate cancer; earlier studies also describe associated risk for breast cancer and lymphoma, though additional studies have not been supportive (Zhang 2012, Cybulski 2013, Gao 2013, Rogoa-Janiszewska 2020, Wokoorczyk 2020, Hu 2021); Also known as 657del5; This variant is associated with the following publications: (PMID: 9590180, 19908051, 23317186, 32255556, 18073374, 24619942, 26929905, 28649662, 29785153, 30426508, 30322717, 30612635, 22131123, 22293976, 25485873, 23765759, 16770759, 23149842, 22941933, 19635536, 14973119, 19452044, 16033915, 27150568, 27038244, 19393249, 27276934, 26083025, 26822949, 25980754, 27616075, 28008555, 26681312, 28374160, 28873162, 28376765, 25186627, 15185344, 11093281, 18606567, 11279524, 16544999, 11953735, 18940477, 12833396, 12505263, 12123493, 10852373, 10398434, 9620777, 29368341, 29915322, 29555771, 29753700, 28152038, 26265251, 31173646, 30590007, 31187634, 31159747, 29419426, 31980526, 33178177, 31589614, 32338768, 33488600, 32441320, 32843899, 24113799, 33077847, 32427313) -

Hereditary cancer-predisposing syndrome Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	May 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2021	The c.657_661delACAAA pathogenic mutation, located in coding exon 6 of the NBN gene, results from a deletion of 5 nucleotides at positions 657 to 661, causing a translational frameshift with a predicted alternate stop codon (p.K219Nfs*16). The c.657_661delACAAA mutation (commonly referred to as 657del5 in the literature) is the most common NBN mutation in Eastern European individuals with Nijmegen Breakage Syndrome (Varon R et al. Eur. J. Hum. Genet., 2000 Nov;8:900-2). This mutation has been reported with increased frequency in individuals with medulloblastoma, prostate cancer, pancreatic cancer, melanoma, breast cancer, colon cancer, and non-Hodgkin's lymphoma (Borecka M et al. Gene, 2016 Aug;587:169-72; Ciara E et al. Acta Neuropathol., 2010 Mar;119:325-34; Cybulski C et al. Cancer Res., 2004 Feb;64:1215-9; Domagala P et al. PLoS ONE, 2015 Jun;10:e0130393; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Lhota F et al. Clin. Genet., 2016 Oct;90:324-33; Steffen J et al. Int. J. Cancer, 2004 Aug;111:67-71). This variant has also been observed, in the homozyous and compound heterozygous state, in patients with Nijmegen Breakage syndrome (Matsuura S et al. Nat Genet, 1998 Jun;19:179-81; Kleier S et al. Clin Genet, 2000 May;57:384-7; Szczauba K et al. J. Appl. Genet., 2012 May;53:189-91). 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. 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). Based on the supporting clinical evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, flagged submission	research	Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 09, 2021	This is a deletion of five base pairs from exon 6 of the NBN mRNA (c.657_661delACAAA), which results in frameshift after codon 219 and creation of a novel stop codon 16 amino acid residues later and would generally be expected to result in an absent or disrupted protein product.This is the most common variant reported in individuals affected with Nijmegen breakage syndrome (NBS), and is considered to be a founder mutation in the Slavic population (PMID: 9590180). It is also known as 657del5 in the literature. Heterozygous carriers may have increased risk for several types of cancers including breast, lymphoma, melanoma, medulloblastoma, prostate and others (PMID: 15185344, 14973119, 18606567, 19908051, 24113799). Experimental studies propose that this deletion encodes a partially functional protein that diminishes the severity of the NBS phenotype (PMID: 11279524). The mutation database Clinvar contains entries for this variant (Variation ID:6940). -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Oct 15, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

Aplastic anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

case-control;clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Mar 04, 2021

- -

Lissencephaly;C4551563:Microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 06, 2015

- -

NBN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2023

The NBN c.657_661del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys219Asnfs*16). The c.657_661del variant (also known as c.657del5) in the NBN gene is a founder pathogenic variant in the Slavic population and causes Nijmegen breakage syndrome in the homozygous state or in combination with another pathogenic variant in NBN (Varon et al. 1998. PubMed ID: 9590180). 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). However, this variant has been reported in up to ~0.04% of individuals (primarily within Europeans) in a large population database of presumably healthy individuals (http://gnomad.broadinstitute.org/variant/8-90983441-ATTTGT-A). In ClinVar, this variant has been classified as pathogenic as well as a risk factor (https://www.ncbi.nlm.nih.gov/clinvar/variation/6940/). 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.Lys219Asnfs*16 variant was identified in 50 of 30494 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic ductal adenocarcinoma, medulloblastoma, prostate cancer, breast cancer, ovarian cancer, non-Hodgkin lymphoma, or colorectal cancer and was present in 20 of 6450 control chromosomes (frequency: 0.003) from healthy individuals (Borecka 2016, Ciara 2010, Cybulski 2004, Domagala 2015, Kraus 2017, Lhota 2016, Steffen 2004, Susswein 2015, Tung 2015). This variant is a Slavic founder mutation with carrier frequency among newborns in the range of 1/154 in the Czech Republic to 1/190 in Poland (Steffen 2004). The variant was also identified in dbSNP (ID: rs587776650 as "With Pathogenic allele"), ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and twelve other submitters), and LOVD 3.0 (4x). The variant was identified in control databases in 55 of 276598 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 50 of 126360 chromosomes (freq: 0.0004), Other in 1 of 6436 chromosomes (freq: 0.0002), Finnish in 2 of 25738 chromosomes (freq: 0.00008), and Latino in 2 of 34324 chromosomes (freq: 0.00006); it was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. 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). The variant has been associated with an increased risk of breast cancer and medulloblastoma, and a significant increase in overall cancer risks (Zhang 2013, Ciara 2010, Gao 2013, Borecka 2016). The c.657_661del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 219 and leads to a premature stop codon at position 234. 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 NBN-associated cancer 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. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 20, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

May 17, 2022

- -

Familial cancer of breast;C0398791:Microcephaly, normal intelligence and immunodeficiency Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 10-26-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776650; hg19: chr8-90983441;