Submissions for variant NM_000059.4(BRCA2):c.7977-1G>C

dbSNP: rs81002874

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV000031714	SCV004101453	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-08	reviewed by expert panel	curation	The c.7977-1G>C variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 17 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, Internal lab contributors). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong).
Invitae	RCV000045368	SCV000073381	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 17 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 present in population databases (rs81002874, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with prostate, ovarian, and breast cancer (PMID: 12474142, 16211554, 22006311, 23479189). This variant is also known as IVS17-1G>C or 8205-1G>C. ClinVar contains an entry for this variant (Variation ID: 38132). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 20020529). Studies have shown that disruption of this splice site results in skipping of exons 17-18 and skipping of exon 18 and introduces a premature termination codon (PMID: 16211554, 22006311). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162588	SCV000213004	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The c.7977-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide before coding exon 17 of the BRCA2 gene. This mutation has been reported in multiple individuals and families with breast and/or ovarian cancer (Tesoriero AA et al. Hum. Mutat. 2005 Nov;26:495; Snape K et al. Breast Cancer Res. Treat. 2012 Jul;134:429-33; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Lai S et al. Sultan Qaboos Univ. Med. J. 2015 Feb;15:e58-70; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586) as well as prostate cancer (Edwards SM et al. Am. J. Hum. Genet. 2003 Jan;72:1-12; Mitra AV et al. BJU Int. 2007 Jun;99:1350-5; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57; Li D et al. Front Biosci. (Landmark Ed). 2013 Jun;18:1445-59). A multifactorial likelihood ratio model that included co-segregation, pathology, co-occurrence, and family history data found this alteration to be pathogenic (Spurdle AB et al. Hum. Mutat. 2010 Feb;31:E1141-5; Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). Of note, this alteration is also designated as IVS17-1G>C in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Splicing analysis has demonstrated c.7977-1G>C results in the production of a primary transcript lacking coding exon 17 (Ambry internal data; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031714	SCV000327781	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031714	SCV000488695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000486971	SCV000568489	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Tesoriero 2005, Fraile-Bethencourt 2017); Observed in multiple families with Hereditary Breast and Ovarian Cancer (Walsh 2011, de Juan Jimenez 2013, Pritzlaff 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 8205-1G>C; This variant is associated with the following publications: (PMID: 25085752, 21769658, 21285146, 25649125, 17063265, 12474142, 20513136, 20736950, 23479189, 22006311, 22527104, 20020529, 20002770, 20043088, 22962691, 22889855, 23747895, 17981615, 27225637, 16211554, 17419707, 28008555, 28339459, 29446198, 30720243, 33084842, 32918181, 31447099, 30787465)
Fulgent Genetics, Fulgent Genetics	RCV000031714	SCV000575741	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507368	SCV000602775	pathogenic	not specified	2016-02-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162588	SCV000683926	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 17 of the BRCA2 gene. RNA studies have shown that this variant causes aberrant transcripts which skip exon 18, resulting in frameshifts and premature translation stop signals (PMID: 22006311, 28339459). This variant has been reported in 8 individuals affected with breast cancer (including 1 male individual), 1 individual affected with both breast and ovarian cancer, 2 individuals affected with ovarian cancer, 2 individuals affected with pancreatic cancer and 4 individuals affected with prostate cancer (PMID: 15728167, 20736950, 22006311, 22527104, 22711857, 23479189, 23569316, 28008555, 32918181, 34500047, Color internal data). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60462 cases and 1/53460 controls (OR=3.537, 95%CI 0.395 to 31.645; p-value=0.38) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000488). This variant has been identified in 2/281032 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486971	SCV000889145	pathogenic	not provided	2021-11-05	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.00004 (2/50340 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast, ovarian, peritoneal, and prostate cancer (PMIDs: 28008555 (2017), 25685387 (2015), 23569316 (2013), 22006311 (2011), 20736950 (2010), 12474142 (2003)). In addition, this variant has been reported to cause aberrant splicing and loss of exon 18 (PMIDs: 28339459 (2017), 16211554 (2005)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045368	SCV000919024	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7977-1G>C is 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: Four predict the variant abolishes a 3' acceptor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing, by showing in a minigene assay several types of aberrant transcripts that exclude exon 18 (partly or fully), and no detectable canonical transcript (Fraile-Bethencourt_2017). The variant allele was found at a frequency of 4e-06 in 249640 control chromosomes (gnomAD). c.7977-1G>C has been reported in the literature in several individuals affected with breast, ovarian, and prostate cancer (e.g. Edwards_2003, Walsh_2011, Snape_2012, Jimenez_2013, Pritzlaff_2017, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. 13 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031714	SCV001434911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-08	criteria provided, single submitter	clinical testing	This c.7977-1G>C variant in intron 17 of the BRCA2 gene is predicted to alter splicing at the acceptor site of exon 18 leading to an abnormal mRNA. This variant has been reported in patients and families with hereditary breast cancer and ovarian cancer (PMID: 16211554, 20020529, 22527104, 23479189) and is rarely observed in general population databases. Therefore, the c.7977-1G>C variant in the BRCA2 gene is classified as pathogenic.
Sema4, Sema4	RCV000162588	SCV002531896	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486971	SCV002761185	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473215	SCV004211951	pathogenic	Familial cancer of breast	2023-09-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031714	SCV000054321	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031714	SCV000147237	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045368	SCV000587925	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483442	SCV004228937	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 10-16-2017 by Lab Color. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.