Submissions for variant NM_000059.4(BRCA2):c.67+1G>A

dbSNP: rs81002796

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218090	SCV000279587	pathogenic	not provided	2015-11-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.67+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the BRCA2 gene. This variant destroys a canonical splice donor site and causes exon 2 skipping, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonatti 2006). This variant, also defined as BRCA2 295+1G>A using alternate nomenclature, has been reported in individuals with a personal and family history of early-onset breast and/or ovarian cancer and has been described as a founder pathogenic variant in the Sephardic Jewish population (Bonatti 2006, Sagi 2011, Balabanski 2014). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077381	SCV000327501	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510076	SCV000608123	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	The c.67+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the BRCA2 gene. This mutation has previously been reported in three families of Sephardic origin affected with breast and/or ovarian cancer (Sagi M et al. Fam. Cancer. 2011 Mar;10(1):59-63). Functional analysis of this alteration using an RNA based assay showed skipping of coding exon 1 and truncation of the BRCA2 protein (Ambry internal data; Bonatti F et al. Cancer Genet. Cytogenet. 2006 Oct;170(2):93-101). Further, an alteration at the same location (c.67+1G>T) has been reported in a German family affected with breast and/or ovarian cancer (Meyer P et al. Hum. Mutat. 2003 Sep;22(3):259). 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.
Invitae	RCV000496390	SCV001591718	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted 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 breast cancer (PMID: 17011978, 21063910, 32058061, 32846166). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 52160). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 17011978, 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496390	SCV002511908	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.67+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon skipping (example, Bonatti_2006). The variant was absent in 250582 control chromosomes. c.67+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003162384	SCV003914731	pathogenic	Familial cancer of breast	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003162384	SCV004210424	pathogenic	Familial cancer of breast	2022-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218090	SCV004220516	pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. It is reported to cause the skipping of exon 2 during splicing, resulting in a truncated protein product (PMID: 17011978 (2006)). 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 with a personal or family history of breast and/or ovarian cancer (PMIDs: 35220195 (2022), 32658311 (2021), 32599251 (2020), 32438681 (2020), 32058061 (2020), 32846166 (2020), 28888541 (2017), 21063910 (2011), and 12938098 (2003)). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077381	SCV000109178	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-11-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077381	SCV000146093	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-06-21	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496390	SCV000587532	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332101	SCV004040594	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research