Submissions for variant NM_000059.4(BRCA2):c.8954-2A>C

dbSNP: rs1135401928

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496263	SCV004489288	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 22 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: 28692638, 31343793, 31825140). ClinVar contains an entry for this variant (Variation ID: 431350). Studies have shown that disruption of this splice site alters BRCA2 gene expression (PMID: 31343793). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 31343793). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496263	SCV000587981	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353886	SCV000592242	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 c.8954-2A>C was not identified in the literature, nor was it identified in any of the following databases: dbSNP, Exome Variant Server ESP Project, HGMD, UMD, LOVD, and COSMIC. This variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant -2 position of the 3' splice consensus sequence. In addition, four in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a greater than 10% difference in splicing, and Myriad classifies this variant as “suspected deleterious” (personal communication). This is the type of variant expected to cause hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.