Submissions for variant NM_007294.4(BRCA1):c.981_982del (p.Thr327_Cys328insTer)

dbSNP: rs80357772

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)	RCV000077636	SCV000282351	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000049211	SCV000077224	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys328*) 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 hereditary breast and ovarian cancer and breast cancer and colon cancer (PMID: 8531968, 22970155, 23479189, 24578176, 24961674, 26026974, 26187060, 26848529, 27257965). This variant is also known as 1100delAT and 981delAT. ClinVar contains an entry for this variant (Variation ID: 55772). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162892	SCV000213379	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The c.981_982delAT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 981 to 982, causing a translational frameshift with a predicted alternate stop codon (p.C328*). This pathogenic mutation has been reported in multiple unrelated individuals with early onset breast and/or ovarian cancer and has been reported as an Asian founder mutation (Kang PC et al. Breast Cancer Res. Treat., 2014 Apr;144:635-42; Angioni S et al. Gynecol Oncol Case Rep, 2014 Aug;9:21-3; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059; Wu X et al. Int. J. Gynecol. Cancer, 2017 10;27:1650-1657; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Wen WX et al. J. Med. Genet., 2018 02;55:97-103; Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475; Li A et al. Gynecol. Oncol., 2018 10;151:145-152; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Deng M et al. Int. J. Cancer, 2019 09;145:1517-1528; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368). This mutation is also referred to as as 1100_1101delAT 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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240695	SCV000265855	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077636	SCV000326480	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162892	SCV000683379	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
GeneDx	RCV000657804	SCV000779559	pathogenic	not provided	2020-07-07	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 or family history consistent with pathogenic variants in this gene (FitzGerald 1996, Thirthagiri 2008, Kwong 2012, Azzollini 2016, Sun 2017, Wu 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database.; Also known as c.1100_1101delAT; This variant is associated with the following publications: (PMID: 22970155, 28724667, 8531968, 23479189, 27257965, 17922413, 24578176, 27062684, 28692638, 26026974, 24961674, 26187060, 18627636, 26848529, 28993434, 29681614, 29086229, 29487695, 30014164, 30078507, 30702160, 30720863, 28176296, 30093976, 30972954, 30309222, 31815095)
3DMed Clinical Laboratory Inc	RCV000240695	SCV000803954	pathogenic	Breast neoplasm	2017-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049211	SCV000918691	pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.981_982delAT (p.Cys328X) 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 (e.g. c.1016dupA (p.Val340fsX6), c.1054G>T (p.Glu352X), c.1091_1092delCT (p.Pro364fsX4)). The variant was absent in 277146 control chromosomes. c.981_982delAT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer (see e.g. Aretini 2003, Wu 2017). These data indicate that the variant is very likely to be associated with disease. A publication also reported experimental evidence that primary (non neoplastic) mammary epithelial cells (obtained from tumour-free women) carrying the variant, were defective in stalled replication fork repair (i.e. suppression of replication stress) that contributes to tumorigenesis in BRCA1-deficient mammary tissue (Pathania 2014). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000077636	SCV004216956	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077636	SCV000109439	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-01-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077636	SCV000143972	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000049211	SCV000587091	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000657804	SCV001906325	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000657804	SCV001968126	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250550	SCV002520902	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
deCODE genetics, Amgen	RCV000077636	SCV004022172	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-21	no assertion criteria provided	research	The variant NM_007294.4:c.981_982del (chr17:43094548) in BRCA1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as pathogenic.