Submissions for variant NM_007294.4(BRCA1):c.697_698del (p.Val233fs)

dbSNP: rs80357747

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031276	SCV000299475	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.
Invitae	RCV000049102	SCV000077115	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val233Asnfs*4) 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, ovarian and colon cancer (PMID: 10644434, 11720839, 14522380, 15477862, 22006311, 26350514, 26787237, 26822237). This variant is also known as 816delGT. ClinVar contains an entry for this variant (Variation ID: 37695). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131861	SCV000186916	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	The c.697_698delGT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 2 nucleotides between positions 697 and 698, causing a translational frameshift with a predicted alternate stop codon (p.V233Nfs*4). This mutation is a known Norwegian founder mutation and has been reported in multiple breast and/or ovarian cancer patients (Heimdal K et al. Eur. J. Cancer 2003 Oct;39(15):2205-13; Bjørge T et al. Br. J. Cancer 2004 Nov;91(10):1829-34; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). One female carrier of this mutation was diagnosed with both breast and ovarian cancer, and the ovarian tumor demonstrated loss of heterozygosity at this allele (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7). Of note, this alteration is also designated as 816delGT 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800320	SCV000296317	pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast, ovarian and colorectal cancers in the published literature and has been reported as a founder mutation in the Norwegian population (PMID: 30730459 (2019), 26822237 (2016), 26787237 (2016), 26350514 (2015), 22006311 (2011), 15477862 (2004), 14522380 (2003), 11720839 (2001), 10644434 (1999)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031276	SCV000326394	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031276	SCV000564337	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131861	SCV000683348	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian and colon cancer (PMID: 9667259, 15477862, 22006311, 26350514, 26787237, 26822237, 30730459) and is known to be a founder mutation in the Norwegian population (PMID: 11720839, 14522380). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049102	SCV000916738	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.697_698delGT (p.Val233AsnfsX4) 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. The variant was absent in 248832 control chromosomes. The variant, c.697_698delGT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, predominantly in Norwegian individuals, and has been indicated to be a Norwegian founder mutation (eg. Moller_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001800320	SCV002757723	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 816_817del, 816delGT; This variant is associated with the following publications: (PMID: 9667259, 15735322, 10644434, 25452441, 22006311, 26350514, 30730459, 26822237, 26787237, 32719484, 29339979, 14522380, 11720839, 28918466, 29371908, 31853058, 28888541, 35165121, 28152038)
Sharing Clinical Reports Project (SCRP)	RCV000031276	SCV000053881	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031276	SCV000145667	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	RCV000049102	SCV000587071	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031276	SCV004244150	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing