Submissions for variant NM_007294.4(BRCA1):c.4603G>T (p.Glu1535Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357366

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077578	SCV000300141	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.
GeneDx	RCV000235132	SCV000210179	pathogenic	not provided	2023-10-29	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 4722G>T; This variant is associated with the following publications: (PMID: 23096355, 29486991, 25525159, 11606101, 26183948, 28503720, 28049106, 22811390, 28127413, 29446198, 31209999, 31447099, 20104584, 23192404, 31892343, 12920083, 35837282, 36974724)
Ambry Genetics	RCV000162879	SCV000213366	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.E1535* pathogenic mutation (also known as c.4603G>T), located in coding exon 13 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4603. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This mutation has been reported in several individuals with breast and/or ovarian cancer and one patient with breast and serous mixed endometrioid cancers (Schorge JO et al. Gynecol. Oncol. 2001 Nov;83:383-7; Pennington KP et al. Cancer. 2013 Jan;119:332-8; Rummel S et al. Breast Cancer Res. Treat. 2013 Jan;137:119-25; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164:593-601; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Barrington DA et al. Gynecol. Oncol. 2018 05;149:337-340). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000077578	SCV000326006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000048603	SCV000540929	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496846	SCV000699159	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-04	criteria provided, single submitter	clinical testing	Variant Summary: The variant in interest, c.4603G>T, is a nonsense mutation that leads to a premature termination at codon 1535. This variant has been reported in the literature and reputable databases at least 15 times and was not identified in large and broad ExAC control cohort. This variant is located in a close proximity to other known pathogenic variants, such as c.4609C>T (p.Gln1537X), c.4612C>T (p.Gln1538X), c.4618G>T (p.Glu1540X) and c.4621G>T (p.Glu1541X). These variants have been reported in UMD, BIC and HGMD at least 7 times with biological significance "5 - Causal", indicating that the variant in interest is located in a mutational hot spot. The variant in interest shows very strong evidence for pathogenicity: it is a truncating variant, located in a mutational hot spot and is absent from controls (ESP and 1000G). Taken together, this variant has been classified as a Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077578	SCV001434961	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-02	criteria provided, single submitter	clinical testing	This c.4603G>T (p.Glu1535*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant is absent in the general population according to the gnomAD database. It has been reported in several unrelated patients with breast cancer or ovary cancer [PMID: 11606101, 22811390].Therefore, the c.4603G>T (p.Glu1535*) variant in the BRCA1 gene is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496846	SCV001585591	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-10	criteria provided, single submitter	clinical testing	Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 55236). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and uterine cancer (PMID: 11606101, 22811390, 26183948, 28503720). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1535*) 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000077578	SCV004013215	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-05	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Baylor Genetics	RCV000077578	SCV004215185	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235132	SCV004224827	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
Color Diagnostics, LLC DBA Color Health	RCV000162879	SCV004360166	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 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 reported in individuals affected with early-onset and/or familial breast cancer (PMID: 11606101, 22811390, 23096355, 26183948, 28503720). 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.
All of Us Research Program, National Institutes of Health	RCV000077578	SCV004817651	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 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 reported in individuals affected with early-onset and/or familial breast cancer (PMID: 11606101, 22811390, 23096355, 26183948, 28503720). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496846	SCV004848530	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Glu1535X variant in BRCA1 has been previously reported in at least 9 individuals with BRCA2-associated cancers (Schorge 2001 PMID:11606101, Ozcelik 2003 PMID:12920083, Pennington 2013 PMID:22811390, Dodova 2015 PMID:26183948, Rummel 2017 PMID:28503720, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, ClinVar Variation ID 55236) and in at least 3 individuals with a family history of breast and ovarian cancer (HBOC) that had undergone clinical genetic testing (Barrington 2018 PMID: 29486991, Rebbeck 2018 PMID: 29446198). It has also been identified in 0.005% (2/41454) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This frequency is low enough to be consistent with the frequency of HBOC in the general population. This nonsense variant leads to a premature termination codon at position 1535, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as pathogenic on Sept 08, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300141.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1.
Sharing Clinical Reports Project (SCRP)	RCV000077578	SCV000109381	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077578	SCV000145126	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	RCV000496846	SCV000587411	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research