Submissions for variant NM_007294.4(BRCA1):c.3178G>T (p.Glu1060Ter)

dbSNP: rs80357424

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077540	SCV000299891	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048092	SCV000076105	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1060*) 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 breast and/or ovarian cancer (PMID: 9333265, 24010542, 26681312). This variant is also known as 3297G>T. ClinVar contains an entry for this variant (Variation ID: 54789). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077540	SCV000195916	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000212171	SCV000210143	pathogenic	not provided	2020-09-14	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; Not observed in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3297G>T; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens 1997, Fostira 2014); This variant is associated with the following publications: (PMID: 22434525, 25525159, 9333265, 29339979, 29446198, 24010542, 26681312, 11504767, 17574839, 29371908, 31209999, 12481264, 24660075, 32719484)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077540	SCV000325570	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000448786	SCV000537659	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-16	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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least 50 individuals and families affected with breast and ovarian cancer (PMID: 9333265, 11504767, 17574839, 24010542, 26681312, 29339979, 29371908) and it is a suspected founder mutation in Norway (PMID: 17574839, 23199084, 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.
Department of Medical Genetics, Oslo University Hospital	RCV000077540	SCV000564339	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212171	SCV000600319	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000448786	SCV000660945	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.E1060* pathogenic mutation (also known as c.3178G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3178. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) families and has been described as a Norwegian founder mutation (Shattuck-Eidens D et al. JAMA. 1997 Oct;278:1242-50; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Soegaard M et al. Clin Cancer Res, 2008 Jun;14:3761-7; Thomassen M et al. Acta Oncol, 2008;47:772-7; Janaviius R. EPMA J. 2010 Sep;1:397-412; Fostira F et al. Case Rep Genet. 2014 Mar;2014:875029; Susswein LR et al. Genet Med, 2016 08;18:823-32; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also referred to as 3297G>T in the 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048092	SCV000918719	pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3178G>T (p.Glu1060X) 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 245534 control chromosomes (gnomAD). The variant, c.3178G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Shattuck-Eidens_1997, Loman_2001, Moller_2001, Fostira_2014). 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212171	SCV001449635	pathogenic	not provided	2016-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077540	SCV004216838	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212171	SCV004238179	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212171	SCV005199732	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077540	SCV000109341	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-02-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077540	SCV000144653	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	RCV000048092	SCV000587283	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358497	SCV001554247	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077540	SCV002589106	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing