NM_000059.4(BRCA2):c.7976+5G>T AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 25, 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:: RCV000582257.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.7976+5G>T]

NM_000059.4(BRCA2):c.7976+5G>T

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+5G>T

HGVS:

NC_000013.11:g.32362698G>T
NG_012772.3:g.52219G>T
NM_000059.4:c.7976+5G>TMANE SELECT
LRG_293t1:c.7976+5G>T
LRG_293:g.52219G>T
NC_000013.10:g.32936835G>T
NM_000059.3:c.7976+5G>T

Links:

dbSNP: rs786201180

NCBI 1000 Genomes Browser:

rs786201180

Molecular consequence:

NM_000059.4:c.7976+5G>T - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000689085	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002676493	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21638052, 24123850, 29969168 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000689085

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 18, 2021)

germline

clinical testing

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

SCV002676493

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 25, 2023)

germline

clinical testing

PubMed (3)
[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

Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing.

Brandão RD, van Roozendaal K, Tserpelis D, Gómez García E, Blok MJ.

Breast Cancer Res Treat. 2011 Oct;129(3):971-82. doi: 10.1007/s10549-011-1599-7. Epub 2011 Jun 3.

PubMed [citation]

PMID:: 21638052

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000689085.4

#	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 to T nucleotide substitution at the +5 position of intron 17 of the BRCA2 gene. This variant is also known as IVS17+5G>T in the literature. Functional RNA studies have shown that this variant causes in-frame skipping of exon 17 (PMID: 29969168, 31191615) resulting in a non-functional protein (PMID: 15695382, 18451181). This variant has been reported in 5 individuals who were affected with breast and/or ovarian cancer from 3 families (PMID: 29969168). 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, SCV002676493.2

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

Description

The c.7976+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 16 in the BRCA2 gene. This variant segregated with breast cancer in three families (Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160; Ambry internal data), and RNA analyses on several probands demonstrated that it results in skipping of coding exon 16 (also referred to as exon 17), which is located in a domain that is important for protein function (Ambry internal data; Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be 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 20, 2024

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