NM_000059.4(BRCA2):c.682-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 15, 2021
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:: RCV001188662.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.682-2A>G]

NM_000059.4(BRCA2):c.682-2A>G

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.682-2A>G

Other names:

IVS8-2A>G

HGVS:

NC_000013.11:g.32330917A>G
NG_012772.3:g.20438A>G
NM_000059.4:c.682-2A>GMANE SELECT
NM_001406719.1:c.682-2A>G
NM_001406720.1:c.682-2A>G
NM_001406721.1:c.682-2A>G
NM_001406722.1:c.313-2A>G
LRG_293t1:c.682-2A>G
LRG_293:g.20438A>G
NC_000013.10:g.32905054A>G
NM_000059.3:c.682-2A>G

Links:

dbSNP: rs878853287

NCBI 1000 Genomes Browser:

rs878853287

Molecular consequence:

NM_000059.4:c.682-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406719.1:c.682-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406720.1:c.682-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406721.1:c.682-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406722.1:c.313-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001355769	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002664193	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 15, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24123850, 26026974 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001355769

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 4, 2020)

germline

clinical testing

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

SCV002664193

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 15, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants.

de Garibay GR, Acedo A, García-Casado Z, Gutiérrez-Enríquez S, Tosar A, Romero A, Garre P, Llort G, Thomassen M, Díez O, Pérez-Segura P, Díaz-Rubio E, Velasco EA, Caldés T, de la Hoya M.

Hum Mutat. 2014 Jan;35(1):53-7. doi: 10.1002/humu.22456. Epub 2013 Oct 28.

PubMed [citation]

PMID:: 24123850

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001355769.2

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

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the BRCA2 gene. RT-PCR analysis from carrier blood RNA showed that the variant allele produced only predicted non-functional transcripts (PMID: 24123850). This variant has been reported in a hereditary breast cancer (PMID: 26026974) and a hereditary breast and ovarian cancer family (PMID: 24123850). In the latter family, this variant segregated in two out of three breast cancer affected members who were tested (PMID: 24123850). 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

From Ambry Genetics, SCV002664193.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.682-2A>G pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration segregated with disease in one family and was observed via RT-PCR to cause aberrant splicing resulting in coding exon 8 skipping (de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7). This alteration was also detected in 1/312 males with breast cancer who also had a positive family history of breast and/or ovarian cancer. (de Juan I et al. Fam Cancer, 2015 Dec;14:505-13). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to 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: Oct 26, 2024

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