Submissions for variant NM_007294.4(BRCA1):c.2934T>G (p.Tyr978Ter)

dbSNP: rs80357115

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031074	SCV000299858	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	RCV000195361	SCV000076030	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr978*) 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 ovarian cancer (PMID: 9667663, 11493753, 17591843, 22399190). This variant is also known as 3053T>G and Tyr1017ter. ClinVar contains an entry for this variant (Variation ID: 37493). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000048017	SCV000210140	pathogenic	not provided	2022-12-27	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 familial breast/ovarian cancer and is considered to be a common pathogenic variant in individuals of Jewish (non-Ashkenazi) ancestry in Iraq and other middle Eastern countries (Theodor et al., 1998; Shiri-Sverdlov et al., 2001; Quintana-Murci et al., 2005; Hall et al., 2009; Laitman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3053T>G; This variant is associated with the following publications: (PMID: 11493753, 11102978, 21913181, 25525159, 29335924, 34657373, 33754277, 26681312, 22430266, 21324516, 17591843, 22399190, 15951957, 19241424, 21305653, 11304778, 21063910, 16140926, 25452441, 26187060, 17148771, 19370767, 18703817, 25788227, 26556299, 26295337, 11139249, 9667663, 17020472, 29310832, 29086229, 34022715, 32843487, 30702160, 30322717, 31825140, 29446198, 36385461, 34157778)
Ambry Genetics	RCV000162860	SCV000213347	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	The p.Y978* pathogenic mutation (also known as c.2934T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 2934. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This mutation has been reported in numerous individuals or families with breast and/or ovarian cancer (Theodor L et al. Br. J. Cancer. 1998 Jun;77:1880-3; Shiri-Sverdlov R et al. Hum. Mutat. 2000 Dec;16:491-501; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Zhang S et al. Gynecol Oncol. 2011 May;121:353-7; Bernstein-Molho R et al. Breast Cancer Res Treat. 2018 02;167:697-702; Bhaskaran SP et al. Int J Cancer. 2019 08;145:962-973; Laitman Y et al. Hum Mutat. 2019 11;40:e1-e23). Two unrelated non-Ashkenazi Jewish ovarian cancer families carrying the p.Y978* alteration were found to share identical haplotypes, indicating a founder effect (Theodor L et al. Br. J. Cancer. 1998 Jun;77(11):1880-3). Of note, this may be referred to as 3053T>G in some literature. This variant was not reported in population-based 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048017	SCV000296282	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMID: 30702160 (2019), 30322717 (2018), 30014164 (2018), 29086229 (2018), 21324516 (2011), and 17591843 (2007)). 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	RCV000031074	SCV000325501	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162860	SCV000683074	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	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 reported in individuals affected with breast and ovarian cancer (PMID: 21324516, 22399190, 25452441, 26681312). 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.
Counsyl	RCV000031074	SCV000785813	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195361	SCV000916718	pathogenic	Hereditary breast ovarian cancer syndrome	2018-02-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2934T>G (p.Tyr978X) 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., p.Pro981fsX19 and p.Asn1002fsX22). The variant was absent in 246118 control chromosomes. The c.2934T>G variant has been reported in the literature in numerous individuals affected with Hereditary Breast and Ovarian Cancer. 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. Seven 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	RCV000031074	SCV004215144	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-22	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031074	SCV000053670	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031074	SCV000144586	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	RCV000195361	SCV000587263	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353980	SCV000591416	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000195361	SCV001749393	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 01-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.