Submissions for variant NM_007294.4(BRCA1):c.2563C>T (p.Gln855Ter)

dbSNP: rs80357131

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031056	SCV000299786	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047880	SCV000075893	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-17	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in a family affected with breast cancer (PMID: 12673801). This variant is also known as 2682C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37475). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln855*) 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). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031056	SCV000195907	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000223464	SCV000277957	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The p.Q855* pathogenic mutation (also known as c.2563C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2563. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in several BRCA1 mutation-positive families (Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031056	SCV000325398	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657621	SCV000779364	pathogenic	not provided	2024-03-18	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 at significant frequency 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 2682C>T; This variant is associated with the following publications: (PMID: 16267036, 25525159, 12673801, 34697415, 19329713, 26843898, 12672316, 26295337, 29446198, 31742824, 33758026)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657621	SCV000887643	pathogenic	not provided	2021-05-23	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast or ovarian cancer in the published literature (PMID: 32420470 (2020), 29446198 (2018), and 12673801 (2003)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047880	SCV000916768	pathogenic	Hereditary breast ovarian cancer syndrome	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2563C>T (p.Gln855X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. p.Ser955X, p.Glu1017X, p.Leu1086X etc.). This variant is absent in 245796 control chromosomes (gnomAD). It has been reported in several HBOC patients/families in literature and clinical databases, including two patients who had early onset breast cancer. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000223464	SCV001360139	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-15	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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least two individuals affected with breast cancer and in suspected hereditary breast and ovarian cancer families (PMID: 12672316, 12673801, 29446198). 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.
Fulgent Genetics, Fulgent Genetics	RCV002496473	SCV002804556	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-07-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031056	SCV000053651	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-10-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031056	SCV000144475	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047880	SCV000587232	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research