NM_000059.4(BRCA2):c.475+2T>C AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 28, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001388345.5

Allele description [Variation Report for NM_000059.4(BRCA2):c.475+2T>C]

NM_000059.4(BRCA2):c.475+2T>C

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.475+2T>C

HGVS:

NC_000013.11:g.32326152T>C
NG_012772.3:g.15673T>C
NM_000059.4:c.475+2T>CMANE SELECT
NM_001406719.1:c.475+2T>C
NM_001406720.1:c.475+2T>C
NM_001406721.1:c.475+2T>C
NM_001406722.1:c.106+2T>C
LRG_293t1:c.475+2T>C
LRG_293:g.15673T>C
NC_000013.10:g.32900289T>C
NM_000059.3:c.475+2T>C

Links:

dbSNP: rs1555280966

NCBI 1000 Genomes Browser:

rs1555280966

Molecular consequence:

NM_000059.4:c.475+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.475+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.475+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.475+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406722.1:c.106+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001589280	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 30883759, 18703817, 24156927, 28102861, 28724667, 29176636, 29446198, 30792206, 16199547, 20104584, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001589280

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 28, 2022)

germline

clinical testing

PubMed (11)
[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

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gómez B, Goina E, Acedo A, Buratti E, Velasco EA.

J Pathol. 2019 Aug;248(4):409-420. doi: 10.1002/path.5268. Epub 2019 Apr 23.

PubMed [citation]

PMID:: 30883759

The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families.

Palma MD, Domchek SM, Stopfer J, Erlichman J, Siegfried JD, Tigges-Cardwell J, Mason BA, Rebbeck TR, Nathanson KL.

Cancer Res. 2008 Sep 1;68(17):7006-14. doi: 10.1158/0008-5472.CAN-08-0599. Epub 2008 Aug 14.

PubMed [citation]

PMID:: 18703817
PMCID:: PMC2752710

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001589280.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30883759). ClinVar contains an entry for this variant (Variation ID: 825144). Disruption of this splice site has been observed in individual(s) with breast cancer, Fanconi anemia, and/or ovarian cancer (PMID: 18703817, 24156927, 28102861, 28724667, 29176636, 29446198, 30792206). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).

#	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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