Submissions for variant NM_000059.4(BRCA2):c.516+1G>C

dbSNP: rs397507762

Total submissions: 5

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	RCV000258169	SCV000327148	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509726	SCV000607866	pathogenic	Hereditary cancer-predisposing syndrome	2017-03-29	criteria provided, single submitter	clinical testing	The c.516+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the BRCA2 gene. This mutation has been previously described in an Italian family with multiple cases of breast cancer (Capalbo C, Ann. Oncol. 2006 Jun; 17 Suppl 7:vii34-40). 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.
GeneDx	RCV000523730	SCV000617462	pathogenic	not provided	2016-04-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.516+1G>C or IVS6+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 6 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 744+1G>C. This 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 reported in a family with hereditary breast cancer (Capalbo 2006). Based on the currently available information, we consider BRCA2 c.516+1G>C to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523730	SCV004219671	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 16760289 (2006), 32438681 (2020)). It has also been reported in a world-wide study of BRCA1/BRCA2 mutation carriers (PMID: 29446198 (2018)). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003529933	SCV004295475	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 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 breast and/or ovarian cancer (PMID: 16760289, 29446198). ClinVar contains an entry for this variant (Variation ID: 51787). 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.