Submissions for variant NM_007294.4(BRCA1):c.3664G>T (p.Glu1222Ter)

dbSNP: rs80357356

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)	RCV000083196	SCV000299990	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	RCV000131817	SCV000186872	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.E1222* pathogenic mutation (also known as c.3664G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3664. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been reported in breast and/or ovarian cancer cohorts (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149(1):31-9; eMERGE Am J Hum Genet. 2019 Sep 5; 105(3): 588-605.). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505832	SCV000296427	pathogenic	not provided	2020-09-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, this variant has been reported in individuals affected with breast cancer in the published literature (PMID: 25428789 (2015), 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083196	SCV000325717	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496663	SCV000699056	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3664G>T (p.Glu1222X) 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 251296 control chromosomes. c.3664G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Churpek_2015, Judkins_2005, and Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000505832	SCV000779361	pathogenic	not provided	2022-06-06	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3783G>T; This variant is associated with the following publications: (PMID: 25428789, 16267036, 26295337, 29446198, 28888541, 31447099, 31219654)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000083196	SCV000839902	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-10-30	criteria provided, single submitter	clinical testing	The c.3664G>T variant is predicted to yield a premature stop codon at amino acid position 1222 of BRCA1 gene, which is one of mechanisms causing BRCA1 defects related breast cancer. This variant is absent in general population (not in gnomad) and observed in multiple breast cancer patients (Breast Cancer Information Core, PMID:25428789). It has been also observed in other clinical labs and reported as a pathogenic. Based on the above evidences, we interpret this variant as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131817	SCV000912035	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-06	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 affected with breast cancer (PMID: 25428789). 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	RCV000496663	SCV001584131	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.Glu1222*) 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 a personal and family history of breast cancer (PMID: 25428789). ClinVar contains an entry for this variant (Variation ID: 54959). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000505832	SCV003917926	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Baylor Genetics	RCV000083196	SCV004211743	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-08-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083196	SCV000115270	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-08-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083196	SCV000144830	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	RCV000496663	SCV000587330	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research