Submissions for variant NM_007294.4(BRCA1):c.3403C>T (p.Gln1135Ter)

dbSNP: rs80357136

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)	RCV000077547	SCV000282307	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	RCV000236027	SCV000292936	pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.3403C>T at the cDNA level and p.Gln1135Ter (Q1135X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3522C>T. 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 has been reported in association with hereditary breast and ovarian cancer (Judkins 2005, Caux-Moncoutier 2011, Gutierrez Espeleta 2012, Kanchi 2014, Maxwell 2017). We consider it to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077547	SCV000325650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574138	SCV000673014	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The p.Q1135* pathogenic mutation (also known as c.3403C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3403. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This pathogenic mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer and/or a family history suggestive of HBOC syndrome (Wagner T et al. Genomics. 1999 Dec;62:369-76; Fernández-Ramires R et al. Br. J. Cancer. 2009 Oct;101:1469-80; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Gutiérrez Espeleta GA et al. Clin. Genet. 2012 Nov;82:484-8; Kanchi KL et al. Nat Commun. 2014;5:3156; Lu C et al. Nat Commun. 2015 Dec;6:10086; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574138	SCV000688435	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	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 multiple individuals affected with breast and/or ovarian cancer (PMID: 21120943, 21895635, 24448499; Color internal data), and has been identified in 12 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/250876 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077547	SCV000839895	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-25	criteria provided, single submitter	clinical testing	The c.3403C>T (p.Gln1135*) variant in the BRCA1 gene has been reported by multiple clinical laboratories in ClinVar and reviewed by an expert panel as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/54868/ ). This variant creates a premature stop codon at amino acid position 1135 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. The variant was detected in one individual from the ExAC database (http://exac.broadinstitute.org/variant/17-41244145-G-A). This variant thus classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496327	SCV000918683	pathogenic	Hereditary breast ovarian cancer syndrome	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3403C>T (p.Gln1135X) 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.Ile1159fsX6 and p.Glu1161fsX3). The variant was absent in 245838 control chromosomes. The c.3403C>T variant has been reported in the literature in multiple 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. 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	RCV000496327	SCV001592385	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1135*) 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/or ovarian cancer (PMID: 16267036, 21120943, 21895635, 24448499). This variant is also known as 3522C>T. ClinVar contains an entry for this variant (Variation ID: 54868). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077547	SCV000109348	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-01-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077547	SCV000144753	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	RCV000496327	SCV000587309	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research