Submissions for variant NM_007294.4(BRCA1):c.2059C>T (p.Gln687Ter)

dbSNP: rs273898674

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111755	SCV000299691	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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240699	SCV000265858	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000216253	SCV000276839	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.Q687* pathogenic mutation (also known as c.2059C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2059. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in multiple Asian hereditary breast and ovarian cancer (HBOC) syndrome families (Worsham MJ et al. Diagn. Mol. Pathol. 1998 Jun;7:164-7; Hasmad HN et al. Gynecol. Oncol. 2016 May;141:318-22; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789). Of note, this mutation is also designated as 2178C>T in published literature. This variant is considered to be rare based on population 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	RCV000111755	SCV000296464	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-06	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111755	SCV000325219	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216253	SCV000912043	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 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.
Invitae	RCV001857389	SCV002177458	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54448). This variant is also known as 2178C>T. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9836072, 29446198, 30702160, 31815095). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln687*) 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).
DASA	RCV000111755	SCV002498798	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-10	criteria provided, single submitter	clinical testing	The c.2059C>T;p.(Gln687*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 54448; PMID: 27257965; 26541979; 26187060; 9836072) - PS4. This variant is not present in population databases (rs273898674- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 9836072) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic
Baylor Genetics	RCV000111755	SCV004216967	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111755	SCV000144282	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354843	SCV001549554	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Gln687X variant was not identified in the literature nor was it identified in the Cosmic, MutDB, UMD-LSDB, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs273898674) as “With Pathogenic allele”, in ClinVar (classified as pathogenic, reviewed by an expert panel 2016, submitters: ENIGMA, CIMBA, Ambry Genetics, BIC, Laboratory of Molecular Diagnosis of Cancer - West China Hospital, Sichuan University and Quest Diagnostics Nichols Institute San Juan Capistrano), in Clinvitae (2x), GeneInsight-COGR (5 clinical laboratories classified as pathogenic), LOVD 3.0 (1x), BIC Database (1x pathogenic), and ARUP Laboratories (definitely pathogenic). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln687X variant leads to a premature stop codon at position 687 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 breast 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.