NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 29, 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:: RCV000131868.20

Allele description [Variation Report for NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter)]

NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter)

Other names:

p.E49*:GAA>TAA

HGVS:

NC_000013.11:g.32319154G>T
NG_012772.3:g.8675G>T
NG_017006.2:g.1210C>A
NM_000059.4:c.145G>TMANE SELECT
NP_000050.2:p.Glu49Ter
NP_000050.3:p.Glu49Ter
LRG_293t1:c.145G>T
LRG_293:g.8675G>T
LRG_293p1:p.Glu49Ter
NC_000013.10:g.32893291G>T
NM_000059.3:c.145G>T
U43746.1:n.373G>T
p.E49*
p.Glu49*
U43746.1:n.373C>T

Note:

The E49X nonsense change results from a G>T change, not the C>T initially reported by BIC.

Nucleotide change:

373G>T

Protein change:

E49*

Links:

dbSNP: rs80358435

NCBI 1000 Genomes Browser:

rs80358435

Molecular consequence:

NM_000059.4:c.145G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186923	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11389159, 17925560, 20215541, 23479189, 24504028 Citation Link,
SCV000903685	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 29, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20927582, 23479189, 24504028, 29446198, 30287823, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186923

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 29, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000903685

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 29, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age.

Bergthorsson JT, Ejlertsen B, Olsen JH, Borg A, Nielsen KV, Barkardottir RB, Klausen S, Mouridsen HT, Winther K, Fenger K, Niebuhr A, Harboe TL, Niebuhr E.

J Med Genet. 2001 Jun;38(6):361-8.

PubMed [citation]

PMID:: 11389159
PMCID:: PMC1734886

BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model.

Vogel KJ, Atchley DP, Erlichman J, Broglio KR, Ready KJ, Valero V, Amos CI, Hortobagyi GN, Lu KH, Arun B.

J Clin Oncol. 2007 Oct 10;25(29):4635-41.

PubMed [citation]

PMID:: 17925560

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000186923.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.E49* pathogenic mutation (also known as c.145G>T), located in coding exon 2 of the BRCA2 gene, results from a G to T substitution at nucleotide position 145. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been reported in multiple breast and/or ovarian cancer kindreds to date (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Vogel KJ et al. J. Clin. Oncol. 2007 Oct;25:4635-41; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Labidi-Galy S et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). Haplotype analysis has identified this alteration as a Chilean founder mutation (Alvarez C et al. Oncotarget. 2017 Sep;8:74233-74243). Of note, this alteration is also designated as 373G>T in published literature. 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. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000903685.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast or ovarian cancer (PMID: 20927582, 23479189, 24504028, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_000017) and has been identified in 54 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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

Last Updated: Oct 26, 2024

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