NM_002485.5(NBN):c.657_661del (p.Lys219fs) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Aug 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000212733.60

Allele description [Variation Report for NM_002485.5(NBN):c.657_661del (p.Lys219fs)]

NM_002485.5(NBN):c.657_661del (p.Lys219fs)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.657_661del (p.Lys219fs)

Other names:

657del5

HGVS:

NC_000008.10:g.90983445_90983449delGTTTT
NC_000008.11:g.89971217_89971221del
NG_008860.1:g.18454_18458del
NM_001024688.3:c.411_415del
NM_002485.5:c.657_661delMANE SELECT
NP_001019859.1:p.Lys137fs
NP_002476.2:p.Lys219fs
LRG_158:g.18454_18458del
NC_000008.10:g.90983442_90983446del
NC_000008.10:g.90983442_90983446delTTTGT
NC_000008.10:g.90983445_90983449del
NC_000008.10:g.90983445_90983449del
NC_000008.10:g.90983445_90983449delGTTTT
NM_002485.4:c.657_661delACAAA
NM_002485.5:c.657_661delACAAAMANE SELECT
NP_002476.2:p.Lys219AsnfsTer15
p.K219NFS*16
p.K219NfsX16
p.Lys219AsnfsX16

Protein change:

K137fs

Links:

OMIM: 602667.0001; dbSNP: rs587776650

NCBI 1000 Genomes Browser:

rs587776650

Molecular consequence:

NM_001024688.3:c.411_415del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002485.5:c.657_661del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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dynein axonemal assembly factor 8 [Homo sapiens]
dynein axonemal assembly factor 8 [Homo sapiens]
gi|59710085|ref|NP_631909.2|

Protein
gag:akt fusion protein [AKT8 retrovirus]
gag:akt fusion protein [AKT8 retrovirus]
gi|210068|gb|AAA42545.1|

Protein
2-isopropylmalate synthase [Grimontella sp. AG753]
2-isopropylmalate synthase [Grimontella sp. AG753]
gi|1397850098|gb|PXW51708.1||gnl|WG I|2770352306

Protein
Homo sapiens DNA cross-link repair 1B (DCLRE1B), transcript variant 1, mRNA
Homo sapiens DNA cross-link repair 1B (DCLRE1B), transcript variant 1, mRNA
gi|296434293|ref|NM_022836.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149712	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 11, 2021)	germline	clinical testing	Citation Link,
SCV000889554	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 22, 2022)	unknown	clinical testing	PubMed (34) [See all records that cite these PMIDs] 11279524, 15185344, 14973119, 18606567, 19908051, 24113799, 9590180, 25485873, 22131123, 22941933, 15279809, 25980754, 26083025, 33471974, 26822949, 27616075, 29368341, 30426508, 31173646, 33471991, 33840814, 34544220, 34072659, 33050356, 34072463, 35309086, 12845677, 22491912, 10848790, 23317186, 9590181, 27150568, 29419426, 26467025
SCV001160103	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 14, 2023)	germline	clinical testing	Citation Link,
SCV001245910	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV002010433	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002018221	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005199284	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	33	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland.

Steffen J, Varon R, Mosor M, Maneva G, Maurer M, Stumm M, Nowakowska D, Rubach M, Kosakowska E, Ruka W, Nowecki Z, Rutkowski P, Demkow T, Sadowska M, Bidziński M, Gawrychowski K, Sperling K.

Int J Cancer. 2004 Aug 10;111(1):67-71.

PubMed [citation]

PMID:: 15185344

NBS1 is a prostate cancer susceptibility gene.

Cybulski C, Górski B, Debniak T, Gliniewicz B, Mierzejewski M, Masojć B, Jakubowska A, Matyjasik J, Złowocka E, Sikorski A, Narod SA, Lubiński J.

Cancer Res. 2004 Feb 15;64(4):1215-9.

PubMed [citation]

PMID:: 14973119

See all PubMed Citations (36)

Details of each submission

From GeneDx, SCV000149712.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889554.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (34)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160103.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245910.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	33	not provided	not provided	clinical testing	not provided

Description

NBN: PVS1, PS3, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		33	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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 proteinâ€™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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010433.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018221.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199284.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001365763	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	flagged submission Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV001365763 appears to be redundant with SCV001365920. (LMM Criteria)	risk factor (May 8, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24113799, 11279524, 9590180, 22131123, 23317186, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001365763

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

flagged submission

Reason: This record appears to be redundant with a more recent record from the same submitter.

Notes: SCV001365763 appears to be redundant with SCV001365920.

(LMM Criteria)

risk factor
(May 8, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Last Updated: Nov 3, 2024

Relating variation to medicine