Submissions for variant NM_000059.4(BRCA2):c.7008-2A>G

dbSNP: rs81002823

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113688	SCV001161561	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.992127
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113688	SCV000327576	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509699	SCV000608012	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The c.7008-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 13 in the BRCA2 gene. In one study, this alteration was detected in a proband with bilateral breast cancer at ages 39 and 46, who also had a family history of early onset breast cancer. An African American woman with breast cancer diagnosed under the age of 45 has also been reported to have this alteration (Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Bonatti F et al. Cancer Genet. Cytogenet. 2006 Oct;170:93-101). Of note, this alteration is also designated as IVS13-2A>G in published literature. This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496680	SCV001585644	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 17011978, 25980754, 29446198). This variant is also known as IVS13-2A>G. ClinVar contains an entry for this variant (Variation ID: 52245). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17011978, 19179552, 22505045, 23451180, 31191615; Invitae). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473393	SCV004210538	pathogenic	Familial cancer of breast	2022-07-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476930	SCV004220532	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families with breast cancer (PMID: 17011978 (2006), 19491284 (2009)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV003476930	SCV004238608	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113688	SCV000146997	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496680	SCV000587880	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000113688	SCV004243750	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing