Submissions for variant NM_007294.4(BRCA1):c.2864C>A (p.Ser955Ter)

dbSNP: rs80357295

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077530	SCV000299845	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000131912	SCV000186967	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	The p.S955* pathogenic mutation (also known as c.2864C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 2864. This changes the amino acid from a serine to a stop codon within coding exon 9. This alteration has been identified in numerous breast/ovarian cohorts from North American, European, Hispanic, African, and Indian families (Weitzel JN et al. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1666-71; Vogel KJ et al. J. Clin. Oncol., 2007 Oct;25:4635-41; Vaidyanathan, K et al. J Biosci. 2009 Sep;34(3):415-22; Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Kwong A et al. J Med Genet, 2016 Jan;53:15-23; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). Of note, this alteration is also designated as 2983C>A in the published 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.
GeneDx	RCV000255164	SCV000321424	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2983C>A; Observed in multiple individuals with personal and/or family history of breast and/or ovarian cancer and has been reported as a recurrent pathogenic variant in the Hispanic population (Weitzel 2005, Vogel 2007, Thomassen 2008, Vaidyanathan 2009, Borg 2010, Fackenthal 2012); This variant is associated with the following publications: (PMID: 26187060, 24312913, 18465347, 25525159, 27286788, 20104584, 26564481, 19805903, 21913181, 25371446, 16030099, 23233716, 22034289, 17925560, 29339979, 29446198)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077530	SCV000325481	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077530	SCV000488025	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-28	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077530	SCV000564361	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-04-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131912	SCV000688406	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast cancer (PMID: 17925560, 19805903, 20104584, 21614564, 22034289, 30350268) and in other suspected hereditary breast and ovarian cancer families (PMID: 16030099, 18465347, 23233716, 29446198, 31209999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255164	SCV000888874	pathogenic	not provided	2021-10-06	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant 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/families with breast and/or ovarian cancer in the published literature (PMIDs: 29446198 (2018), 19805903 (2009), 17925560 (2007), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496521	SCV001362815	pathogenic	Hereditary breast ovarian cancer syndrome	2019-07-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2864C>A (p.Ser955X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251560 control chromosomes. c.2864C>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (including Borg_2010, Fackenthal_2012, Heramb_2018, Litton_2011, Thomassen_2008, Vaidyanathan_2009, Vogel_2007, Weitzel_2005). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000496521	SCV001587211	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser955*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 16030099, 19805903, 20104584, 26187060, 29339979, 29446198). This variant is also known as 2983C>A. ClinVar contains an entry for this variant (Variation ID: 54701). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077530	SCV000109331	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-09-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077530	SCV000144563	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077530	SCV000207334	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-06	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496521	SCV000587258	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research