NM_000059.4(BRCA2):c.8951C>A (p.Ser2984Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 16, 2022
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:: RCV001018541.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.8951C>A (p.Ser2984Ter)]

NM_000059.4(BRCA2):c.8951C>A (p.Ser2984Ter)

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.8951C>A (p.Ser2984Ter)

Other names:

9179C>A

HGVS:

NC_000013.11:g.32379513C>A
NG_012772.3:g.69034C>A
NM_000059.4:c.8951C>AMANE SELECT
NP_000050.2:p.Ser2984Ter
NP_000050.3:p.Ser2984Ter
LRG_293t1:c.8951C>A
LRG_293:g.69034C>A
LRG_293p1:p.Ser2984Ter
NC_000013.10:g.32953650C>A
NM_000059.3:c.8951C>A
p.Ser2984X

Protein change:

S2984*

Links:

dbSNP: rs80359146

NCBI 1000 Genomes Browser:

rs80359146

Molecular consequence:

NM_000059.4:c.8951C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001179793	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 22, 2018)	germline	clinical testing	Citation Link,
SCV001340969	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 16, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8988179, 12649099, 16644204, 22798144, 28205045, 31837001, 32019277, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001179793

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 22, 2018)

germline

clinical testing

Citation Link,

SCV001340969

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 16, 2022)

germline

clinical testing

PubMed (8)
[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 of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D.

Nat Genet. 1997 Jan;15(1):103-5.

PubMed [citation]

PMID:: 8988179

Predictive testing for BRCA1 and 2 mutations: a male contribution.

Daly PA, Nolan C, Green A, Ormiston W, Cody N, McDevitt T, O'hIci B, Byrne D, McDermott E, Carney DN, O'Higgins N, Barton DE.

Ann Oncol. 2003 Apr;14(4):549-53.

PubMed [citation]

PMID:: 12649099

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV001179793.4

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

Description

The p.S2984* pathogenic mutation (also known as c.8951C>A), located in coding exon 21 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8951. This changes the amino acid from a serine to a stop codon within coding exon 21. 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, SCV001340969.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant causes a C to A nucleotide substitution resulting in a nonsense mutation at codon 2984 in the BRCA2 protein. The variant creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, a nonsense mutation at this codon caused by a different single-nucleotide substitution has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 8988179, 12649099, 16644204, 22798144, 28205045, 31837001, 32019277). 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: Sep 29, 2024

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