Submissions for variant NM_007294.4(BRCA1):c.1600C>T (p.Gln534Ter)

dbSNP: rs142074233

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)	RCV000238846	SCV000323333	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000236467	SCV000293472	pathogenic	not provided	2017-09-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1600C>T at the cDNA level and p.Gln534Ter (Q534X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as BRCA1 1719C>T using alternate nomenclature, has been observed in at least three families presenting with breast and/ or ovarian cancer (Machackova 2008). We consider BRCA1 Gln534Ter to be a pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236467	SCV000296406	pathogenic	not provided	2020-01-11	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238846	SCV000325103	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781028	SCV000918788	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1600C>T (p.Gln534X) 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 (eg. p.Gln541X, p.Gly559fsX13, p.Gln563X). The variant was absent in 245682 control chromosomes. c.1600C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Li_2018, Machackova_2008). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781028	SCV001590634	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-29	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: 54303). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (HBOC) or undergoing testing for HBOC (PMID: 18489799, 29446198, 30078507). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln534*) 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).
Ambry Genetics	RCV002399410	SCV002709149	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	The p.Q534* pathogenic mutation (also known as c.1600C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1600. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been detected in multiple patients with HBOC-related cancers (Machackova et al. BMC Cancer 2008 May;8:140; Li et al. Gynecol. Oncol. 2018 10;151(1):145-152; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620; Vocka et al. Cancers (Basel) 2019 May;11(6)). 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.
Baylor Genetics	RCV000238846	SCV004216930	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002399410	SCV004361053	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least one individual each affected with breast or ovarian cancer (PMID: 30078507, 33471991; Leiden Open Variation Database DB-ID BRCA1_004147) and in at least seven families suspected to be affected with hereditary breast and ovarian cancer (PMID: 18489799, 29446198, 31409081). 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.
CZECANCA consortium	RCV001270966	SCV001451770	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000238846	SCV004244120	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing