Submissions for variant NM_000059.4(BRCA2):c.517-1G>A

dbSNP: rs81002849

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131857	SCV000186912	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-09	criteria provided, single submitter	clinical testing	The c.517-1G>A intronic pathogenic mutation (also known as 745-1G>A or IVS6-1G>A) results from a G to A substitution one nucleotide before coding exon 6 of the BRCA2 gene. This mutation has been reported in an Arab individual diagnosed with breast cancer at age 33 who had no family history of cancer (Tazzite A et al. Gynecol Oncol. 2012 Jun;125(3):687-92). This mutation was shown to cause the skipping of coding exon 6 (described as exon 7) by RT-PCR analysis (Menendez M et al. Breast Cancer Res Treat. 2012 Apr;132(3):979-92). This alteration is also shown to result in the loss of a single nucleotide at the 5' end of coding exon 6 in the mRNA (Ambry internal data; 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). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000113730	SCV000296616	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-22	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113730	SCV000327156	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000709290	SCV000838735	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000709290	SCV001578220	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted 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 breast cancer (PMID: 22425665). ClinVar contains an entry for this variant (Variation ID: 51800). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 30883759; Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001588865	SCV001814715	pathogenic	not provided	2021-02-18	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in exon 7 skipping, leading to a null allele in a gene for which loss-of-function is a known mechanism of disease (Menndez 2012, Fraile-Bethencourt 2019); Observed in an individual with breast cancer (Tazzite 2012); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 745-1G>A; This variant is associated with the following publications: (PMID: 30883759, 29446198, 24606420, 23697973, 30263132, 26295337, 22425665, 21735045)
Baylor Genetics	RCV003460589	SCV004216042	pathogenic	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113730	SCV000147049	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing