Submissions for variant NM_000059.4(BRCA2):c.8331+1G>A

dbSNP: rs81002837

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212272	SCV000210469	pathogenic	not provided	2018-07-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 IVS18+1G>A or c.8331+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 18 of the BRCA2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in men and women with breast cancer (Zhang 2012, Pritzlaff 2017). Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000166511	SCV000217311	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The c.8331+1G>A intronic variant (also known as IVS18+1G>A) results from a G to A one nucleotide after coding exon 17 of the BRCA2 gene. This alteration was previously reported in 1/409 Chinese breast cancer patients with at least one first or second degree relatives with breast and/or ovarian cancer or with bilateral breast cancer diagnosed under the age of 50 (Zhang J, Breast Cancer Res. Treat. 2012 Apr; 132(2):421-8). 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. RNA studies have demonstrated that this alteration results in substantial, but incomplete splice defects as ascertained by multiple quantitative analyses (Ambry internal data; Gelli E et al. Cancers (Basel), 2019 Mar;11; Nix P et al. Fam Cancer, 2021 Jan;). Furthermore, the close match alteration BRCA2 c.8331+2T>C was observed in individuals who collectively do not present with a clinical history seen in typical high-risk hereditary breast and ovarian cancer (HBOC) variant carriers (Nix P et al. Fam Cancer, 2021 Jan;). However, these data cannot rule out the possibility of a hypomorphic variant with atypical risks. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031737	SCV000327867	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001390937	SCV001592840	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.8331+1G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 19619314, 28339459). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 38154). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 21614564, 26681312, 28008555). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 18 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).
Baylor Genetics	RCV002250494	SCV004210474	pathogenic	Familial cancer of breast	2022-10-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031737	SCV000054344	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-01-07	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250494	SCV002520841	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only