Submissions for variant NM_007294.4(BRCA1):c.2138C>G (p.Ser713Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357233

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031032	SCV000299705	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	RCV000047730	SCV000075743	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser713*) 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 present in population databases (rs80357233, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 11139249, 21913181, 22430266). This variant is also known as 2257C>G. ClinVar contains an entry for this variant (Variation ID: 37451). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074571	SCV000108656	pathogenic	not provided	2023-10-03	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 a personal or family history consistent with pathogenic variants in this gene (PMID: 11139249, 22430266, 21913181, 25722380, 27469594, 30968603); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2257C>G; This variant is associated with the following publications: (PMID: 25400221, 32211327, 28888541, 25525159, 15829246, 26848529, 25722380, 21913181, 22430266, 11139249, 27150160, 27469594, 30702160, 30720243, 30968603, 29625052, 26689913, 32719484, 32341426, 31825140, 29339979, 30078507, 29446198, 28176296, 28724667, 35864222, 34981296, 36451132)
Ambry Genetics	RCV000162851	SCV000213338	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-29	criteria provided, single submitter	clinical testing	The p.S713* pathogenic mutation (also known as c.2138C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2138. This changes the amino acid from a serine to a stop codon within coding exon 9. This mutation was previously identified in individuals and families with breast and/or ovarian cancer diagnoses (Vaziri SA et al. Hum. Mutat. 2001;17:74; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Shi T et al. Int. J. Cancer 2017 05;140:2051-2059; Bhaskaran SP et al. Int. J. Cancer 2019 Jan). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 2257C>G in published literature. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000031032	SCV000266027	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074571	SCV000296379	pathogenic	not provided	2021-01-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. It has been reported in families affected with breast/ovarian cancer in the published literature (PMID: 11139249 (2001), 29446198 (2018), 30702160 (2019)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA1 related cancers.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031032	SCV000325263	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031032	SCV000564388	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047730	SCV000698921	pathogenic	Hereditary breast ovarian cancer syndrome	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2138C>G (p.Ser713X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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. c.2157dupA. p.Glu720fsX6; c.2197_2201delGAGAA, p.Glu733fsX5; c.2241delC, p.Asp749fsX4). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/122388 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in numerous affected individuals in the literature. Functional studies have demonstrated a reduction on multiple aspects of BRCA1 function attributed to this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162851	SCV000911170	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-16	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 and families affected with breast and/or ovarian cancer (PMID: 11139249, 21913181, 22762150, 26845104, 28724667, 30702160, 31825140), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001833). This variant has been identified in 2/282518 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.
Fulgent Genetics, Fulgent Genetics	RCV002477031	SCV002795346	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074571	SCV003809746	pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031032	SCV004212688	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031032	SCV004818223	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	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 and families affected with breast and/or ovarian cancer (PMID: 11139249, 21913181, 22762150, 26845104, 28724667, 30702160, 31825140), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001833). This variant has been identified in 2/282518 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000074571	SCV005199742	pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031032	SCV000053626	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-11-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031032	SCV000144310	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	RCV000047730	SCV000587190	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research