Submissions for variant NM_007294.4(BRCA1):c.3748G>T (p.Glu1250Ter)

dbSNP: rs28897686

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019241	SCV000300004	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.
Invitae	RCV000048311	SCV000076324	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1250*) 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 (rs28897686, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894491, 12497638, 24504028, 24728189). This variant is also known as 3867G>T. ClinVar contains an entry for this variant (Variation ID: 17672). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074586	SCV000108671	pathogenic	not provided	2021-10-21	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 (Castilla 1994, Ahmad 2012, Cunningham 2014, Weren 2016); Not observed at a significant frequency 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 3867G>T; This variant is associated with the following publications: (PMID: 25556971, 22009639, 12497638, 8990217, 9625424, 26843898, 27534398, 9544766, 28152038, 26689913, 26681312, 28263838, 28301456, 18413725, 22469508, 27767231, 22486713, 24504028, 29446198, 30720243, 30322717, 7894491, 25525159, 32719484, 32272925)
Ambry Genetics	RCV000131811	SCV000186866	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The p.E1250* pathogenic mutation (also known as c.3748G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3748. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been identified in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Castilla L et al. Nat. Genet. 1994 Dec;8:387-91; Valarmathi MT et al. Hum Mutat, 2003 Jan;21:98-9; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Shirts BH et al. Genet Med, 2016 10;18:974-81; Weren RD et al. Hum. Mutat. 2017 Feb;38:226-235; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Lecarpentier J et al. Breast Cancer Res, 2012 Jul;14:R99). Of note, this alteration is also designated as 3867G>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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000019241	SCV000266030	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074586	SCV000296296	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	The BRCA1 c.3748G>T (p.Glu1250*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals/families with breast and/or ovarian cancer (PMID: 31815095 (2019), 30322717 (2018), 27767231 (2017), 26843898 (2016), 26681312 (2015), 24504028 (2014), 22009639 (2012), 20104584 (2010)), as well as various other cancer types including colon cancer, stomach cancer, and glioma (PMID: 29625052 (2018), 26689913 (2015), 26681312 (2015)). The frequency of this variant in the general population, 0.000008 (2/251234 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019241	SCV000325737	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000465125	SCV000540952	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000048311	SCV000588048	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506391	SCV000602708	pathogenic	not specified	2017-01-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000019241	SCV000677650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131811	SCV000683129	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-22	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 observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 7894491, 12497638, 18413725, 20104584, 21120943, 22469508, 22486713, 24504028, 26681312, 26845104, 27062684, 27767231; DOI: 10.21203/rs.3.rs-591403/v1, 10.21203/rs.3.rs-122156/v1) and also colon and stomach cancer and low-grade glioma (PMID: 26689913, 26681312). This variant has been identified in 80 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/) and in a breast cancer case-control meta-analysis in 4/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001240). This variant has been identified in 2/251234 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	RCV000048311	SCV000699068	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-23	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3748G>T (p.Glu1250X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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.3904G>T/p.Glu1302X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121388 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple affected individuals and functional study showed variant with ~10% of relative HDR activity in comparison to WT BRCA1 (Lu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000019241	SCV000743401	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019241	SCV000744626	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074586	SCV002021643	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131811	SCV002538242	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Baylor Genetics	RCV000019241	SCV004212755	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-25	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048311	SCV004228099	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-05	criteria provided, single submitter	clinical testing
OMIM	RCV000019241	SCV000039529	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019241	SCV000109357	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-04-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019241	SCV000144858	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	RCV000048311	SCV000587340	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074586	SCV000591470	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Glu1250X variant has been previously observed in our lab in 2 individuals with breast and ovarian cancer. It has also been reported in the literature in 9/522 proband chromosomes of individuals with breast cancer or HBOC; although no control chromosomes were tested to establish the variant's frequency in the general population (Castilla_1994, Eng_2001, Rohlfs_1997, Swisher_2008, Thompson_2012, Tian_2000). The variant has also been identified in the UMD (n=19), BIC (n=47), Exome Server and BOCs databases. In the UMD and BIC databases, the variant was described as being causal and of important clinical significance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897686) but no frequency information was provided therefore not very informative for assessing the population frequency. The variant leads to a premature stop codon at position 1250 which is predicted to cause premature truncation of the protein product. This is a loss of function variant and loss of function is an established disease mechanism for the BRCA1 gene. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019241	SCV000733619	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074586	SCV001906418	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074586	SCV001958637	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019241	SCV002589112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing