NM_000059.4(BRCA2):c.8364G>A (p.Trp2788Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 28, 2024
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:: RCV000216791.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.8364G>A (p.Trp2788Ter)]

NM_000059.4(BRCA2):c.8364G>A (p.Trp2788Ter)

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.8364G>A (p.Trp2788Ter)

HGVS:

NC_000013.11:g.32370434G>A
NG_012772.3:g.59955G>A
NM_000059.4:c.8364G>AMANE SELECT
NP_000050.2:p.Trp2788Ter
NP_000050.3:p.Trp2788Ter
LRG_293t1:c.8364G>A
LRG_293:g.59955G>A
LRG_293p1:p.Trp2788Ter
NC_000013.10:g.32944571G>A
NM_000059.3:c.8364G>A

Protein change:

W2788*

Links:

dbSNP: rs397507981

NCBI 1000 Genomes Browser:

rs397507981

Molecular consequence:

NM_000059.4:c.8364G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV000274881	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000906578	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24010542, 26028024, 29446198, 31853058, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274881

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 25, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000906578

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 28, 2024)

germline

clinical testing

PubMed (5)
[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

Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO).

Lecarpentier J, Noguès C, Mouret-Fourme E, Gauthier-Villars M, Lasset C, Fricker JP, Caron O, Stoppa-Lyonnet D, Berthet P, Faivre L, Bonadona V, Buecher B, Coupier I, Gladieff L, Gesta P, Eisinger F, Frénay M, Luporsi E, Lortholary A, Colas C, Dugast C, Longy M, et al.

Breast Cancer Res. 2012 Jul 3;14(4):R99. doi: 10.1186/bcr3218.

PubMed [citation]

PMID:: 22762150
PMCID:: PMC3680948

High prevalence of BRCA1 founder mutations in Greek breast/ovarian families.

Konstantopoulou I, Tsitlaidou M, Fostira F, Pertesi M, Stavropoulou AV, Triantafyllidou O, Tsotra E, Tsiftsoglou AP, Tsionou C, Droufakou S, Dimitrakakis C, Fountzilas G, Yannoukakos D.

Clin Genet. 2014 Jan;85(1):36-42. doi: 10.1111/cge.12274. Epub 2013 Oct 20.

PubMed [citation]

PMID:: 24010542

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000274881.7

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

Description

The p.W2788* pathogenic mutation (also known as c.8364G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8364. This changes the amino acid from a tryptophan to a stop codon within coding exon 18. This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Thomassen et al. Acta Oncol 2008;47(4):772-7; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Sun et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Labidi-Galy et al. Clin. Cancer Res. 2018 01;24(2):326-333; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620; Bhaskaran et al. Int. J. Cancer 2019 Aug;145(4):962-973; Fostira et al. J. Med. Genet. 2019 Jul; Wang et al. Mol Genet Genomic Med 2019 Jun;7(6):e677). Of note, this alteration is also designated as 8592G>A 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, SCV000906578.4

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

Description

This variant changes 1 nucleotide in exon 19/27 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 detected in at least 11 individuals affected with breast or ovarian cancer (PMID: 24010542, 26028024) and over 40 suspected hereditary breast and ovarian cancer families (PMID: 29446198). This variant alsohas been reported in a multifactorial analysis with a likelihood ratio for pathogenicity based on personal and family history of 0.975 from log(LR)=-0.011170717 for two carriers (PMID: 31853058). This variant has not been identified 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: May 16, 2025

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