Submissions for variant NM_000059.4(BRCA2):c.8009C>A (p.Ser2670Ter)

dbSNP: rs80359035

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000239017	SCV000324610	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239017	SCV000296564	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-27	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000239017	SCV000327795	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569299	SCV000661413	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-16	criteria provided, single submitter	clinical testing	The p.S2670* pathogenic mutation (also known as c.8009C>A), located in coding exon 17 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8009. This changes the amino acid from a serine to a stop codon within coding exon 17. This mutation was identified in a hereditary breast cancer family (Sinilnikova OM et al. Fam. Cancer, 2006;5:15-20) and one study demonstrated that this mutation triggered nonsense-mediated mRNA decay (Ware MD et al. Oncogene, 2006 Jan;25:323-8). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000496340	SCV001587431	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Experimental studies have shown that this nonsense change generates aberrant transcripts that are lacking exon 18 (PMID: 28339459). Additional studies have shown a reduction in mRNA transcripts in cells carrying this variant suggesting that these aberrant transcripts are subject to nonsense-mediated decay (PMID: 16170354). This variant has been reported in an individual affected with breast cancer (PMID: 16528604, 16170354). ClinVar contains an entry for this variant (Variation ID: 52470). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser2670*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
Sharing Clinical Reports Project (SCRP)	RCV000239017	SCV000297560	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-10-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496340	SCV000587930	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research