Submissions for variant NM_007294.4(BRCA1):c.2293G>T (p.Glu765Ter)

dbSNP: rs80357449

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111818	SCV000299739	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	RCV000162853	SCV000213340	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-29	criteria provided, single submitter	clinical testing	The p.E765* pathogenic mutation (also known as c.2293G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2293. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in a Norwegian population (Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3) and in one Hispanic family from the United States (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505829	SCV000296386	pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. It 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 with a personal and/or family history of breast or ovarian cancer (PMIDs: 29446198 (2018) and 29339979 (2018)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111818	SCV000325314	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000111818	SCV000564366	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162853	SCV000683022	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-07	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 an individual with personal and/or family history of BRCA1-associated cancers (PMID: 29339979). 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.
Invitae	RCV001388815	SCV001589964	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu765*) 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. ClinVar contains an entry for this variant (Variation ID: 54524). This premature translational stop signal has been observed in individual(s) with elevated risk for hereditary breast and/or ovarian cancer (PMID: 29339979, 29446198). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001388815	SCV001983624	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2293G>T (p.Glu765X) 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 251086 control chromosomes (gnomAD). c.2293G>T has been reported in the literature in individuals with personal and/or family history of breast/ovarian cancer (e.g. Heramb_2018, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000505829	SCV004100316	pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. female patient with ovarian cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111818	SCV000144368	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing