Submissions for variant NM_000059.4(BRCA2):c.793+1G>A

gnomAD frequency: 0.00001  dbSNP: rs81002846

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045345	SCV000073358	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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). This variant is present in population databases (rs81002846, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer and with pancreatic cancer (PMID: 23961350, 29093764, 29446198, 29483665, 29506128). ClinVar contains an entry for this variant (Variation ID: 52437). 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). For these reasons, this variant has been classified as Pathogenic.
GeneKor MSA	RCV000239312	SCV000296840	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This mutation, which occurs in the first base of intron 9 of the BRCA2 gene, results in incorrect splicing of the mRNA produced by this allele and alteration of the reading frame. This mutation has been described in international bibliography (http://research.nhgri.nih.gov/), as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112827	SCV000327763	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045345	SCV000591712	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568255	SCV000665937	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-17	criteria provided, single submitter	clinical testing	The c.793+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals from breast, ovarian, and pancreatic cancer cohorts (Lowery M et al. J. Natl. Cancer Inst. 2018 10;110(10):1067-1074; Rebbeck T et al. Hum. Mutat. 2018 05;39(5):593-620; Teixeira N et al. Eur. J. Hum. Genet. 2018 06;26(6):848-857; Tsaousis G et al. BMC Cancer 2019 Jun;19(1)). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, a close match alteration, BRCA2 c.793+1G>T results in skipping of coding exon 8 (also called Exon 9) by minigene analysis (Fraile-Bethencourt E et al. J. Pathol., 2019 08;248:409-420). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000568255	SCV000689081	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 9 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A variant at the same position, 793+1G>T, has been reported in RNA studies to result in exon 9 skipping and a premature translation stop signal (PMID: 30883759). This variant has been reported in four individuals affected with breast and/or ovarian cancer (PMID: 31125106, 35264596, 36980780, 3723905) and in four families among the CIMBA participants (PMID: 29446198). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.862, 1.07, 1.050 and 0.920, respectively (PMID: 31131967). This variant has been identified in 1/31208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Mendelics	RCV000045345	SCV000838747	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310169	SCV001499764	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568255	SCV002531892	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000239312	SCV003814327	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112827	SCV003932760	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	affects a donor splice site in intron 9 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52437) with 8 submissions describing this variant as either pathogenic or likely pathogenic. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as pathogenic.
Baylor Genetics	RCV003473409	SCV004210505	pathogenic	Familial cancer of breast	2022-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112827	SCV004839142	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 9 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A variant at the same position, 793+1G>T, has been reported in RNA studies to result in exon 9 skipping and a premature translation stop signal (PMID: 30883759). This variant has been reported in four individuals affected with breast and/or ovarian cancer (PMID: 31125106, 35264596, 36980780, 3723905) and in four families among the CIMBA participants (PMID: 29446198). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.862, 1.07, 1.050 and 0.920, respectively (PMID: 31131967). This variant has been identified in 1/31208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000239312	SCV005196947	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000568255	SCV005901891	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-03	criteria provided, single submitter	clinical testing	PVS1, PM2_Supporting, PP1_Moderate c.793+1G>A, located in a canonic splicing site of the BRCA2 gene, is predicted to alter splicing, probably causing the skipping of exon 9 (PVS1). It is not present in the population database gnomAD v2.1.1 (non-cancer, exome only subset)(PM2_supporting). The variant cosegregates with the disease (LR=18.6)(PMID:31131967)(PP1_Moderate). In addition, it was identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (1x likely pathogenic, 9x pathogenic) and LOVD (5x pathogenic). Based on currently available information, c.793+1G>A is classified as a pathogenic variant according to ClinGen-BRCA1 and BRCA2 Guidelines version v1.0.0.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112827	SCV000145738	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing