Submissions for variant NM_000059.4(BRCA2):c.7976+1G>A

dbSNP: rs81002873

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)	RCV000077419	SCV001161564	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 = 0.999776
Ambry Genetics	RCV000131083	SCV000186013	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The c.7976+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 16 of the BRCA2 gene. This alteration has been detected in multiple breast cancer families (Palma MD et al. Cancer Res. 2008 Sep 1;68(17):7006-14; Li WF et al. Breast Cancer Res Treat. 2008 Jul;110(1):99-109). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A minigene assay demonstrated that this alteration results in complete skipping of coding exon 16 (designated as exon 17 by the authors) (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical and experimental 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.
GeneDx	RCV000235799	SCV000293485	pathogenic	not provided	2022-08-20	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in the in-frame deletion of exon 17, impacting BRCA2 function (Wu 2005, Fraile-Bethencourt 2017); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.8204+1G>A; This variant is associated with the following publications: (PMID: 27157322, 18703817, 31131967, 29922827, 25525159, 17851763, 28339459, 29969168, 28993434, 29446198, 31825140, 30702160, 30078507, 32665702, 15695382)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077419	SCV000327775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388428	SCV001589416	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened 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 or at high risk of breast and/or ovarian cancer (PMID: 17851763, 18703817, 22970155, 28993434, 29446198). ClinVar contains an entry for this variant (Variation ID: 52452). Studies have shown that disruption of this splice site results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 28339459, 31191615; Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Leu2653Pro) have been determined to be pathogenic (PMID: 22678057, 29061967; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001388428	SCV001653084	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-30	criteria provided, single submitter	clinical testing	The c.7976+1G>A variant in BRCA2 has been reported in at least 6 individuals with BRCA2-associated cancers (Li 2018 PMID: 30078507, Wen 2018 PMID:28993434, additional studies summarized in Bhaskaran 2019 PMID: 30702160). Additionally, it was identified in several "high risk" individuals with a personal or family history of BRCA1/2 associated cancers that have undergone clinical genetic testing (Palma 2008 PMID: 18703817, Kwong 2016 PMID: 26187060, Rebbeck 2018 PMID: 29446198). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies show that this variant causes skipping of exon 17 leading to an in-frame deletion of 56 amino acids (Fraile-Bethencourt 2017 PMID: 28339459) that represents less than 10% of the BRCA2 protein. This variant was classified as pathogenic on June 18, 2019 by the ClinGen-approved ENIGMA expert panel (SCV001161564.1). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1_Moderate, PS4_Moderate, PM2_Supporting, PS3_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV000131083	SCV001736052	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-22	criteria provided, single submitter	clinical testing	This variant causes a G>A change at the +1 position in intron 17 of the BRCA2 gene. Functional RNA studies have shown that this variant and a similar splice site variant, c.7976+2C>G, resulted in the skipping of exon 17 and exons 17 and 18, causing the partial deletion of the DNA binding/OB tower domain of the BRCA2 protein and a frameshift, respectively (PMID: 28339459, 31843900). The in-frame deleted protein region contains 5 pathogenic missense variants reported in ClinVar (variation ID: 52423, 38125, 52430, 52455, 38131), which suggests that this region may be functionally important. The variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer and a family with strong history of breast/ovarian cancer (PMID: 17851763, 18703817, 31131967). 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. Based on available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000235799	SCV005041819	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Sharing Clinical Reports Project (SCRP)	RCV000077419	SCV000109217	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-11-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077419	SCV000147233	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-20	no assertion criteria provided	clinical testing