Submissions for variant NM_000059.4(BRCA2):c.8331+2T>C

dbSNP: rs398122602

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258355	SCV000327868	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000258355	SCV000605691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000519723	SCV000617474	likely pathogenic	not provided	2020-12-24	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, however published functional and RNA studies are conflicting showing both aberrant splicing resulting in skipping of exon 18 and normal splicing, as well as both aberrant and wildtype transcript expression (Fraile-Bethencourt 2017, Gelli 2019, Wangensteen 2019, Wai 2020); Not observed in large population cohorts (Lek 2016); Also known as 8559+2T>G; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer referred for genetic testing at GeneDx and in published literature (Cunningham 2014, Tung 2015, Kwong 2018, Fanale 2020, Rumford 2020); This variant is associated with the following publications: (PMID: 29487695, 32123317, 25186627, 28339459, 30832263, 31143303, 24504028, 29339979, 29446198, 30702160, 31131967, 32854451, 32098980, 31209999, 32380732)
Color Diagnostics, LLC DBA Color Health	RCV000581266	SCV000689116	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +2 position of intron 18 splice donor site of the BRCA2 gene. RNA studies have shown that this variant results in the production of several aberrant transcripts that lack (i) exon 18, (ii) exon 17 and 18, or (iii) partial exon 17 and exon 18 (PMID: 28339459, 30832263, 33469799). These transcripts are not expected to produce a functional protein, however, it was noted that the slicing defect may be incomplete (PMID: 30832263, 33469799; ClinVar SCV001178672.2). This variant has been reported in over ten individuals affected with breast and/or ovarian cancer (PMID: 18779604, 24728189, 25186627, 28339459, 30832263, 31131967, 33469799, 35464868; communication with an external laboratory). 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. Incomplete splicing defect attributed to this variant suggests that this variant may be associated with reduced penetrance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496246	SCV000759096	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 24504028, 25186627, 29339979, 29446198, 29487695). ClinVar contains an entry for this variant (Variation ID: 267692). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000581266	SCV001178672	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-03-14	criteria provided, single submitter	clinical testing	The c.8331+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 17 in the BRCA2 gene. This alteration has been reported in multiple hereditary breast and/or ovarian cohorts (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet. 2014 Sep;23(17):4703-9; Kwong A et al. Oncotarget 2018 Jan;9(8):7832-7843; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3). This nucleotide position is highly conserved in available vertebrate species. Several variants at this splice donor site demonstrated substantial but incomplete abnormal splicing in multiple different RNA analyses (Ambry internal data; Fraile-Bethencourt E et al. PLoS Genet, 2017 Mar;13:e1006691; Gelli E et al. Cancers (Basel), 2019 Mar;11; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Nix P et al. Fam Cancer, 2022 Jan;21:7-19). However, at least one recent RNA study has reported no aberrant splicing in association with this variant (Wai HA. Genet Med. 2020 Jun;22(6):1005-1014). In addition, this alteration 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, 2022 Jan;21:7-19). 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000496246	SCV002025847	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000581266	SCV002531933	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000519723	SCV003814482	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000519723	SCV004024416	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463731	SCV004214585	pathogenic	Familial cancer of breast	2021-04-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000519723	SCV004220598	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 24504028 (2014)), and in individuals with breast cancer (PMID: 25186627 (2015), 29487695 (2018), 30130155 (2018), 30702160 (2019), 32854451 (2020), 35464868 (2022)). In large breast cancer association studies, this variant was found in individuals affected with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). Functional splicing assays demonstrate this this variant causes aberrant splicing and skipping of exon 18 and/or partial exon 17 and exon 18, creating a premature stop codon (PMID: 28339459 (2017), 30832263 (2019), 31143303 (2019), 33469799 (2021)). However, production of the normal transcript was also demonstrated (PMID: 30832263 (2019), 32123317 (2020), 33469799 (2021)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000258355	SCV004829267	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-05	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. This prediction has been confirmed by functional studies (PMID: 28339459, 31143303). Aberrant splicing and/or loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer syndrome (PMID: 24504028, 29339979, 24728189, 29487695). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496246	SCV004848283	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.8331+2T>C variant in BRCA2 has been reported in at least 2 probands with BRCA2-related cancer (Cunningham 2014, Tung 2015). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 267692). 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 confirm that this variant leads to abnormal splicing (Fraile-Bethencourt 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000519723	SCV005197324	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496246	SCV000587947	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000258355	SCV002588921	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing