NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Sep 8, 2016
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000077257.25

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]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000109054	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Jul 13, 2011)	germline	clinical testing
SCV000146248	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (Jan 26, 2005)	germline	clinical testing
SCV000146249	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline	clinical testing
SCV000220745	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Sep 26, 2014)	unknown	literature only	PubMed (3) [See all records that cite these PMIDs] 23479189, 20215541, 11389159 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000300300	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015))	Pathogenic (Sep 8, 2016)	germline	curation	ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000326558	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000605677	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004243637	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Mar 2, 2020)	germline	clinical testing
SCV004846378	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20927582, 23479189, 24504028, 29446198, 30287823, 33471991, 25741868
SCV005045983	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2024)	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	yes	10	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	52	not provided	108544	not provided	clinical testing, curation
not provided	germline	not provided	17	not provided	not provided	17	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Latin American, Caribbean	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
Western European, Latin American, Caribbean	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western Europeanan, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients.

Sanz DJ, Acedo A, Infante M, Durán M, Pérez-Cabornero L, Esteban-Cardeñosa E, Lastra E, Pagani F, Miner C, Velasco EA.

Clin Cancer Res. 2010 Mar 15;16(6):1957-67. doi: 10.1158/1078-0432.CCR-09-2564. Epub 2010 Mar 9.

PubMed [citation]

PMID:: 20215541

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

See all PubMed Citations (9)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000109054.3

#	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	germline	not provided	17	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided
2	not provided	2	not provided	not provided	clinical testing	not provided
3	not provided	2	not provided	not provided	clinical testing	not provided
4	Caucasian	1	not provided	not provided	clinical testing	not provided
5	Caucasian	4	not provided	not provided	clinical testing	not provided
6	Central/Eastern European	1	not provided	not provided	clinical testing	not provided
7	Latin American, Caribbean	1	not provided	not provided	clinical testing	not provided
8	Western European	5	not provided	not provided	clinical testing	not provided
9	Western European, Latin American, Caribbean	1	not provided	not provided	clinical testing	not provided
10	Western Europeanan, Central/Eastern European	1	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	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided
6	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided
9	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
10	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000220745.2

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

#	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 Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000300300.2

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

Description

Variant allele predicted to encode a truncated non-functional protein.

#	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 Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000326558.4

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	52	not provided

From Department of Medical Genetics, Oslo University Hospital, SCV000605677.3

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

From BRCAlab, Lund University, SCV004243637.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004846378.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	108544	not provided	not provided		1	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV005045983.1

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

Description

PVS1; PM5_PTC_Strong

#	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

Last Updated: Oct 26, 2024

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