NM_002485.5(NBN):c.803del (p.Thr268fs) AND Microcephaly, normal intelligence and immunodeficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003230977.1

Allele description [Variation Report for NM_002485.5(NBN):c.803del (p.Thr268fs)]

NM_002485.5(NBN):c.803del (p.Thr268fs)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.803del (p.Thr268fs)

HGVS:

NC_000008.11:g.89970457del
NG_008860.1:g.19215del
NM_001024688.3:c.557del
NM_002485.5:c.803delMANE SELECT
NP_001019859.1:p.Thr186fs
NP_002476.2:p.Thr268Serfs
NP_002476.2:p.Thr268fs
LRG_158t1:c.803del
LRG_158:g.19215del
LRG_158p1:p.Thr268Serfs
NC_000008.10:g.90982685del
NM_002485.4:c.803delC

Protein change:

T186fs

Molecular consequence:

NM_001024688.3:c.557del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002485.5:c.803del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Microcephaly, normal intelligence and immunodeficiency (NBS)
Synonyms:: IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY; SEEMANOVA SYNDROME II; Nijmegen breakage syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009623; MedGen: C0398791; Orphanet: 647; OMIM: 251260

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003929288	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29922827, 16415040 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003929288

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.

Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, Lilyquist J, Na J, Moore R, Antwi SO, Bamlet WR, Chaffee KG, DiCarlo J, Wu Z, Samara R, Kasi PM, McWilliams RR, Petersen GM, Couch FJ.

JAMA. 2018 Jun 19;319(23):2401-2409. doi: 10.1001/jama.2018.6228.

PubMed [citation]

PMID:: 29922827
PMCID:: PMC6092184

Mild Nijmegen breakage syndrome phenotype due to alternative splicing.

Varon R, Dutrannoy V, Weikert G, Tanzarella C, Antoccia A, Stöckl L, Spadoni E, Krüger LA, di Masi A, Sperling K, Digweed M, Maraschio P.

Hum Mol Genet. 2006 Mar 1;15(5):679-89. Epub 2006 Jan 13.

PubMed [citation]

PMID:: 16415040

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929288.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: NBN c.803delC (p.Thr268SerfsX8) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251324 control chromosomes. To our knowledge, c.803delC has not been reported in the literature in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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

Last Updated: Jun 10, 2023

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