Submissions for variant NM_007294.4(BRCA1):c.1054G>T (p.Glu352Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357472

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)	RCV000111532	SCV000299527	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	RCV000162843	SCV000213330	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	The p.E352* pathogenic mutation (also known as c.1054G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1054. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer syndrome, specifically from Indian, Japanese, and French Canadian cohorts (Sekine M et al. Clin. Cancer Res. 2001 Oct;7:3144-50; Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Belanger MH et al. J Ovarian Res 2015 Mar;8:1; Maxwell KN et al. Nat Commun, 2017 08;8:319; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Of note, this alteration is also designated as 1173G>T in published literature. 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.
GeneDx	RCV000235441	SCV000292508	pathogenic	not provided	2018-12-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.1054G>T at the cDNA level and p.Glu352Ter (E352X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as BRCA1 1173G>T using alternate nomenclature, has been reported in at least four individuals with a personal and/or family history of breast and/or ovarian cancer (Sekine 2001, Simard 2007, Thirthagiri 2008, Belanger 2015) and is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111532	SCV000324940	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235441	SCV000600236	pathogenic	not provided	2017-03-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162843	SCV000904134	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1, creating a translational termination signal. This variant is expected to cause an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 11595708, 16905680, 18627636, 24249303, 25884701, 28294317, 28831036, 29176636, 29446198). This variant has been identified in 2/251202 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781023	SCV000918783	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1054G>T (p.Glu352X) 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. The variant was absent in 131808 control chromosomes (gnomAD). c.1054G>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Nakamura_2013, Thirthagiri_2008, Simard_2007, Sekine_2001, Lang_2017, Maxwell_2017). 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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781023	SCV001590403	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu352*) 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 present in population databases (rs80357472, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 11595708, 18627636, 25884701, 28831036). ClinVar contains an entry for this variant (Variation ID: 54108). For these reasons, this variant has been classified as Pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV000111532	SCV004042793	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-04	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111532	SCV000143989	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing