Submissions for variant NM_000059.4(BRCA2):c.8755-1G>C

dbSNP: rs81002812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485251	SCV000564799	likely pathogenic	not provided	2017-02-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8755-1G>C or IVS21-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 21 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8983-1G>C. This variant destroys a canonical splice acceptor 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 not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA2 c.8755-1G>C to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485251	SCV000600821	likely pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510081	SCV000607957	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-07-19	criteria provided, single submitter	clinical testing	The c.8755-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 21 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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 likely pathogenic.
Counsyl	RCV000576379	SCV000677879	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865423	SCV002246366	pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 21 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 a personal and/or family history of breast and ovarian cancer (PMID: 9971877, 18489799, 24156927, 32994724). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418090). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 9971877, 23451180, 25382762). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005010383	SCV005633986	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-03-13	criteria provided, single submitter	clinical testing