NM_002485.5(NBN):c.156_157del (p.Ser53fs) AND Microcephaly, normal intelligence and immunodeficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 18, 2023
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:: RCV000410370.15

Allele description [Variation Report for NM_002485.5(NBN):c.156_157del (p.Ser53fs)]

NM_002485.5(NBN):c.156_157del (p.Ser53fs)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.156_157del (p.Ser53fs)

HGVS:

NC_000008.10:g.90994964_90994965del
NC_000008.11:g.89982738_89982739del
NG_008860.1:g.6935_6936del
NM_001024688.3:c.-141_-140del
NM_002485.5:c.156_157delMANE SELECT
NP_002476.2:p.Ser53fs
LRG_158:g.6935_6936del
NC_000008.10:g.90994964_90994965del
NC_000008.10:g.90994964_90994965delAA
NC_000008.10:g.90994966_90994967del
NM_002485.4:c.156_157delTT
NM_002485.5:c.156_157del

Links:

dbSNP: rs767454740

NCBI 1000 Genomes Browser:

rs767454740

Molecular consequence:

NM_001024688.3:c.-141_-140del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_002485.5:c.156_157del - 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
SCV000486614	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 7, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000553052	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9590180, 16415040, 24549055, 28492532
SCV000838320	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV002045379	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A.

Cell. 1998 May 1;93(3):467-76.

PubMed [citation]

PMID:: 9590180

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

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000486614.2

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

#	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 Invitae, SCV000553052.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ser53Cysfs*9) 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 (rs767454740, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 371121). For these reasons, this variant has been classified as 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

From Mendelics, SCV000838320.2

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

#	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 Genome-Nilou Lab, SCV002045379.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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