NM_000059.4(BRCA2):c.7976+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 6, 2023
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:: RCV000131083.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.7976+1G>A]

NM_000059.4(BRCA2):c.7976+1G>A

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.7976+1G>A

HGVS:

NC_000013.11:g.32362694G>A
NG_012772.3:g.52215G>A
NM_000059.4:c.7976+1G>AMANE SELECT
NM_001406719.1:c.7880+1G>A
NM_001406720.1:c.7976+1G>A
NM_001406721.1:c.3044+1G>A
NM_001406722.1:c.1559+1G>A
LRG_293t1:c.7976+1G>A
LRG_293:g.52215G>A
NC_000013.10:g.32936831G>A
NM_000059.3:c.7976+1G>A
U43746.1:n.8204+1G>A

Nucleotide change:

IVS17+1G>A

Links:

Breast Cancer Information Core (BIC) (BRCA2): 8204+1&base_change=G to A; dbSNP: rs81002873

NCBI 1000 Genomes Browser:

rs81002873

Molecular consequence:

NM_000059.4:c.7976+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.7880+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.7976+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.3044+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406722.1:c.1559+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000186013	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25525159, 28339459 Citation Link,
SCV001736052	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186013

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 6, 2023)

germline

clinical testing

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

Citation Link,

SCV001736052

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 22, 2020)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18.

Fraile-Bethencourt E, Díez-Gómez B, Velásquez-Zapata V, Acedo A, Sanz DJ, Velasco EA.

PLoS Genet. 2017 Mar;13(3):e1006691. doi: 10.1371/journal.pgen.1006691.

PubMed [citation]

PMID:: 28339459
PMCID:: PMC5384790

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000186013.9

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

Description

The c.7976+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 16 of the BRCA2 gene. This alteration has been detected in multiple breast cancer families (Palma MD et al. Cancer Res. 2008 Sep 1;68(17):7006-14; Li WF et al. Breast Cancer Res Treat. 2008 Jul;110(1):99-109). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A minigene assay demonstrated that this alteration results in complete skipping of coding exon 16 (designated as exon 17 by the authors) (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical and experimental data presented in the literature, 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 classified 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, SCV001736052.1

#	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 a G>A change at the +1 position in intron 17 of the BRCA2 gene. Functional RNA studies have shown that this variant and a similar splice site variant, c.7976+2C>G, resulted in the skipping of exon 17 and exons 17 and 18, causing the partial deletion of the DNA binding/OB tower domain of the BRCA2 protein and a frameshift, respectively (PMID: 28339459, 31843900). The in-frame deleted protein region contains 5 pathogenic missense variants reported in ClinVar (variation ID: 52423, 38125, 52430, 52455, 38131), which suggests that this region may be functionally important. The variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer and a family with strong history of breast/ovarian cancer (PMID: 17851763, 18703817, 31131967). 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. Based on 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: Oct 26, 2024

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