Submissions for variant NM_007294.4(BRCA1):c.2197G>T (p.Glu733Ter)

dbSNP: rs397508949

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)	RCV000077511	SCV000299714	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077511	SCV000325283	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000479672	SCV000568421	pathogenic	not provided	2022-11-25	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; Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (Litton et al., 2012; Rebbeck et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 2316G>T; This variant is associated with the following publications: (PMID: 29446198, 21913181)
Ambry Genetics	RCV000509808	SCV000607901	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-27	criteria provided, single submitter	clinical testing	The p.E733* pathogenic mutation (also known as c.2197G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2197. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in at least one family with breast and/or ovarian cancer (Litton JK et al. Cancer, 2012 Jan;118:321-5). This mutation was also 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	RCV001852989	SCV002229436	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu733*) 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 clinical features of hereditary breast and ovarian cancer syndrome (PMID: 21913181, 29446198). ClinVar contains an entry for this variant (Variation ID: 54494). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000479672	SCV003809790	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001852989	SCV003923029	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2197G>T (p.Glu733X) 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 250628 control chromosomes (gnomAD). c.2197G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Litton_2012, 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. Six ClinVar submitters, including one expert panel (ENIGMA) and one consortium (CIMBA), have assessed the variant since 2014: all six classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000077511	SCV004216973	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479672	SCV004222589	pathogenic	not provided	2022-08-19	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 breast cancer (PMID: 33471991 (2021), PMID: 21913181 (2012)). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077511	SCV000109311	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-25	no assertion criteria provided	clinical testing