NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 20, 2024
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:: RCV002354232.9

Allele description [Variation Report for NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)]

NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)

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.581G>A (p.Trp194Ter)

HGVS:

NC_000013.11:g.32326563G>A
NG_012772.3:g.16084G>A
NM_000059.4:c.581G>AMANE SELECT
NP_000050.2:p.Trp194Ter
NP_000050.3:p.Trp194Ter
LRG_293t1:c.581G>A
LRG_293:g.16084G>A
LRG_293p1:p.Trp194Ter
NC_000013.10:g.32900700G>A
NM_000059.3:c.581G>A
U43746.1:n.809G>A
p.Trp194*

Nucleotide change:

809G>A

Protein change:

W194*

Links:

dbSNP: rs80358809

NCBI 1000 Genomes Browser:

rs80358809

Molecular consequence:

NM_000059.4:c.581G>A - 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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FAM189A1 AND (alive[prop]) (581)
Gene
HLA-DPB1 AND (alive[prop]) (137)
Gene
Transcriptional factor B3 family protein [Arabidopsis thaliana]
Transcriptional factor B3 family protein [Arabidopsis thaliana]
gi|15236028|ref|NP_194891.1|

Protein
WASHC2A AND (alive[prop]) (182)
Gene
PRRC1 proline rich coiled-coil 1 [Homo sapiens]
PRRC1 proline rich coiled-coil 1 [Homo sapiens]
Gene ID:133619

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002650781	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 20, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21719596, 23983145, 8673091 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002650781

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 20, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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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

A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay.

Biswas K, Das R, Alter BP, Kuznetsov SG, Stauffer S, North SL, Burkett S, Brody LC, Meyer S, Byrd RA, Sharan SK.

Blood. 2011 Sep 1;118(9):2430-42. doi: 10.1182/blood-2010-12-324541. Epub 2011 Jun 30.

PubMed [citation]

PMID:: 21719596
PMCID:: PMC3167357

Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements.

Di Giacomo D, Gaildrat P, Abuli A, Abdat J, Frébourg T, Tosi M, Martins A.

Hum Mutat. 2013 Nov;34(11):1547-57. doi: 10.1002/humu.22428. Epub 2013 Sep 18.

PubMed [citation]

PMID:: 23983145

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002650781.2

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

Description

The p.W194* pathogenic mutation (also known as c.581G>A), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 581. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been detected in a familial breast cancer kindred and shown increase exon skipping in vitro (Couch FJ et al. Nat. Genet., 1996 May;13:123-5; Di Giacomo D et al. Hum. Mutat., 2013 Nov;34:1547-57; Biswas K et al. Blood, 2011 Sep;118:2430-42). Of note, this alteration is also known as 809G>A and Trp194X 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

Last Updated: Aug 25, 2024

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