NM_002485.5(NBN):c.2206G>T (p.Glu736Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 25, 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:: RCV001014726.5

Allele description [Variation Report for NM_002485.5(NBN):c.2206G>T (p.Glu736Ter)]

NM_002485.5(NBN):c.2206G>T (p.Glu736Ter)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.2206G>T (p.Glu736Ter)

HGVS:

NC_000008.11:g.89937054C>A
NG_008860.1:g.52618G>T
NM_001024688.3:c.1960G>T
NM_002485.5:c.2206G>TMANE SELECT
NP_001019859.1:p.Glu654Ter
NP_002476.2:p.Glu736Ter
NP_002476.2:p.Glu736Ter
LRG_158t1:c.2206G>T
LRG_158:g.52618G>T
LRG_158p1:p.Glu736Ter
NC_000008.10:g.90949282C>A
NM_002485.4:c.2206G>T

Protein change:

E654*

Links:

dbSNP: rs756831345

NCBI 1000 Genomes Browser:

rs756831345

Molecular consequence:

NM_001024688.3:c.1960G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002485.5:c.2206G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Nucleotide
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001175471	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15758953, 30287823, 32963463 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001175471

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 25, 2023)

germline

clinical testing

PubMed (3)
[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

Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.

Falck J, Coates J, Jackson SP.

Nature. 2005 Mar 31;434(7033):605-11. Epub 2005 Mar 2.

PubMed [citation]

PMID:: 15758953

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001175471.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.E736* variant (also known as c.2206G>T), located in coding exon 15 of the NBN gene, results from a G to T substitution at nucleotide position 2206. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theNBN gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 19 amino acids of the protein. The exact functional effect of this alteration is unknown; however, this alteration disrupts the C-terminus of the NBN protein which has been shown to be necessary for binding to the ATM protein (Falck J et al. Nature. 2005 Mar;434:605-11). This alteration was observed with an allele frequency of 0.028 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.089 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0010 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was also identified in a cohort of Chinese gastric adenocarcinoma patients (Ji K et al. Chin J Cancer Res. 2020 Aug;32:508-515). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: Sep 29, 2024

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