Submissions for variant NM_000059.4(BRCA2):c.7617+1G>A

dbSNP: rs397507922

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083138	SCV000282250	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-15	reviewed by expert panel	curation	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7436_7617del transcript (encoding predicted non-functional protein).
Invitae	RCV000045259	SCV000073272	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 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 and/or ovarian cancer (PMID: 21184276, 24123850). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52362). Studies have shown that disruption of this splice site results in skipping of exon 15 and introduces a premature termination codon (PMID: 18712473, 21184276, 24123850). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083138	SCV000327692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486153	SCV000568483	pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7617+1G>A or IVS15+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7845+1G>A or 7829+1G>A. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing and several assays have identified that this variant results in abnormal splicing leading to skipping of exon 15 and a truncated protein (Bergthorsson 2001, Thomassen 2011, de Garibar 2014). This variant has been reported in association with breast and ovarian cancer and is a frequently observed variant in Danish and Spanish individuals (Bergthorsson 2001, Gutierrez-Enriquez 2009, Thomassen 2011, Zhang 2011, de Juan Jimenez 2013, de Garibay 2014, Roed Nielsen 2016). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045259	SCV000592128	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000083138	SCV000605707	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579436	SCV000683893	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. RNA studies have shown that this variant causes skipping of exon 15, resulting in premature truncation (PMID: 11389159, 21184276, 24123850, 31191615). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 11389159, 20927582, 21184276, 24123850, 26187060, 26360800, 26833046) or pancreatic cancer (PMID: 12097290, 17301269). 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.
Mendelics	RCV000045259	SCV000838856	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579436	SCV001189045	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The c.7617+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been described as a Danish founder pathogenic mutation and it segregates strongly with disease in many Danish families (Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Roed Nielsen H et al. Acta Oncol, 2016 Sep;55:38-44; Nielsen HR et al. Fam. Cancer, 2016 Oct;15:507-12 ). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses using patient RNA and minigene assays have shown this alteration results in complete loss of exon 15 (Ambry internal data; Bergthorsson JT et al. J. Med. Genet., 2001 Jun;38:361-8; Gutiérrez-Enríquez S et al. Breast Cancer Res. Treat., 2009 Sep;117:461-5; Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; de Garibay GR et al. Hum Mutat, 2014 Jan;35:53-7). Of note, this alteration is also designated as IVS15+1G>A and 7845+1G>A in published literature. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486153	SCV002551568	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473403	SCV004210462	pathogenic	Familial cancer of breast	2022-11-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083138	SCV000115212	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-12-29	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083138	SCV004243775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing