Submissions for variant NM_007294.4(BRCA1):c.2389G>T (p.Glu797Ter)

dbSNP: rs62625306

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)	RCV000019252	SCV000282278	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.
GeneDx	RCV000212169	SCV000210131	pathogenic	not provided	2015-04-27	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.2389G>T at the cDNA level and p.Glu797Ter (E797X) 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, also known as 2508G>T using alternative nomenclature, has been reported in association with familial breast cancer and ovarian cancer (Liede 1998, Yang 2011) and is considered pathogenic.
Ambry Genetics	RCV000162856	SCV000213343	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-14	criteria provided, single submitter	clinical testing	The p.E797* pathogenic mutation (also known as c.2389G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2389. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in numerous individuals with breast and/or ovarian cancer (Yang D et al. JAMA. 2011 Oct;306:1557-65: Walker LC et al. Eur J Hum Genet. 2017 04;25:432-438; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). A Scottish woman diagnosed with breast cancer at age 35 was found to carry this mutation as well as a BRCA2 frameshift mutation (Liede A et al. Am. J. Hum. Genet. 1998 Jun;62(6):1543-4). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000496416	SCV000219217	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-23	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019252	SCV000325340	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019252	SCV000564298	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000019252	SCV000785826	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769717	SCV000901137	pathogenic	Breast and/or ovarian cancer	2022-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162856	SCV000911642	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/250564 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.
Invitae	RCV000496416	SCV001591701	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17682). This variant is also known as G2508T. This premature translational stop signal has been observed in individual(s) with breast cancer or ovarian cancer (PMID: 9585617, 21990299, 26681312, 27836010, 28831036). This sequence change creates a premature translational stop signal (p.Glu797*) 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).
Sema4, Sema4	RCV000162856	SCV002538116	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	curation
Baylor Genetics	RCV000019252	SCV004216837	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-10	criteria provided, single submitter	clinical testing
OMIM	RCV000019252	SCV000039540	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-06-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019252	SCV000109316	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-12-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019252	SCV000144400	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	RCV000496416	SCV000587209	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212169	SCV000591384	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Glu797X variant was identified in a Canadian individual of Scottish descent diagnosed with breast cancer at age 35, who also carried a pathogenic BRCA2 mutation (c.3068dupA, alias BIC 3295insA), making her the first double (compound) heterozygote outside of the Ashkenazi Jewish population (Liede1998, Rebbeck 2016). The variant was also identified as a somatic mutation in a study looking at 429 ovarian cancer cases (frequency of 0.0023) and was not seen in 557 Causcasian controls (Kanchi 2014). The variant has also been identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs rs62625306) as “With Pathogenic, Uncertain significance allele” but no frequency information was provided, Clinvitae database (classification pathogenic), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic), the ClinVar database (classification pathogenic, reviewed by an expert panel, submitters: ENIGMA, CIMBA, GeneDx, Ambry Genetics, OMIM, SCRP, and BIC, classification not provided by Invitae), GeneInsight COGR database (classification pathogenic, by 4 clinical laboratories), the BIC database (unavailable), and UMD (3x with a ”unclassified variant” classification).The p.Glu797X variant leads to a premature stop codon at position 797, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. REFERENCES: Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, Zhang Q, Koboldt DC, Xie M, Kandoth C, McMichael JF, Wyczalkowski MA, Larson DE, Schmidt HK, Miller CA, Fulton RS, Spellman PT, Mardis ER, Druley TE, Graubert TA, Goodfellow PJ, Raphael BJ, Wilson RK, Ding L. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156. doi: 10.1038/ncomms4156. PubMed PMID: 24448499; PubMed Central PMCID: PMC4025965. Liede A, Rehal P, Vesprini D, Jack E, Abrahamson J, Narod SA. A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2. Am J Hum Genet. 1998 Jun;62(6):1543-4. PubMed PMID: 9585617; PubMed Central PMCID: PMC1377168. Rebbeck TR, Friebel TM, Mitra N, Wan F, Chen S, Andrulis IL, Apostolou P, Arnold N, Arun BK, Barrowdale D, Benitez J, Berger R, Berthet P, Borg A, Buys SS, Caldes T, Carter J, Chiquette J, Claes KB, Couch FJ, Cybulski C, Daly MB, de la Hoya M, Diez O, Domchek SM, Nathanson KL, Durda K, Ellis S; EMBRACE., Evans DG, Foretova L, Friedman E, Frost D, Ganz PA, Garber J, Glendon G, Godwin AK, Greene MH, Gronwald J, Hahnen E, Hallberg E, Hamann U, Hansen TV; HEBON., Imyanitov EN, Isaacs C, Jakubowska A, Janavicius R, Jaworska-Bieniek K, John EM, Karlan BY, Kaufman B, Investigators K, Kwong A, Laitman Y, Lasset C, Lazaro C, Lester J, Loman N, Lubinski J, Manoukian S, Mitchell G, Montagna M, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Offit K, Olah E, Olopade OI, Park SK, Piedmonte M, Radice P, Rappaport-Fuerhauser C, Rookus MA, Seynaeve C, Simard J, Singer CF, Soucy P, Southey M, Stoppa-Lyonnet D, Sukiennicki G, Szabo CI, Tancredi M, Teixeira MR, Teo SH, Terry MB, Thomassen M, Tihomirova L, Tischkowitz M, Toland AE, Toloczko-Grabarek A, Tung N, van Rensburg EJ, Villano D, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Zidan J, Zorn KK, McGuffog L, Easton D, Chenevix-Trench G, Antoniou AC, Ramus SJ. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res. 2016 Nov 11;18(1):112. PubMed PMID: 27836010; PubMed Central PMCID: PMC5106833.