Submissions for variant NM_007294.4(BRCA1):c.2071del (p.Arg691fs)

dbSNP: rs80357688

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031025	SCV000282272	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167861	SCV000075712	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg691Aspfs*10) 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 family history of breast and/or ovarian cancer (PMID: 9482581, 9667259, 10486320, 21324516, 24504028). This variant is also known as 2190delA. ClinVar contains an entry for this variant (Variation ID: 37444). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131404	SCV000186380	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The c.2071delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2071, causing a translational frameshift with a predicted alternate stop codon (p.R691Dfs*10). This mutation has been observed in multiple breast and/or ovarian cancer families (Andersen TI et al. Hum. Mutat. 1998;11:166-74; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Jongsma AP et al. Mol Pathol, 2002 Oct;55:305-9; Judkins T et al. Cancer Res, 2005 Nov;65:10096-103; Konecny M et al. Breast Cancer Res Treat. 2011 Feb;126:119-30; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Akbari MR et al. Clin. Genet. 2014 Jan;85:64-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Torres-Mejía G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Pal T et al. Cancer. 2015 Dec;121:4173-80) and in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 2190delA and 2187delA in the 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.
GeneDx	RCV000047699	SCV000210019	pathogenic	not provided	2023-02-23	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 2190delA; This variant is associated with the following publications: (PMID: 21324516, 10486320, 24728189, 23942203, 19471317, 9482581, 17148771, 23569316, 26287763, 24504028, 25371446, 25452441, 23458327, 25556971, 11437066, 17369502, 27534398, 28127413, 33646313, 30875412, 24950059, 34347777, 31897316, 35186721, 27533253, 24830819, 26295337, 33758026)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031025	SCV000325224	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031025	SCV000487819	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-18	criteria provided, single submitter	clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India	RCV000031025	SCV000583989	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-07	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000167861	SCV000588038	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000031025	SCV000593692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131404	SCV000683010	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). 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	RCV000167861	SCV000698915	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-11	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2071delA (p.Arg691Aspfs) 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.2138C>G, p.Ser713X; c.2157dupA, p.Glu720fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121338 control chromosomes. This variant was reported in multiple patients with HBOC (Judkins_2005, Trujillano_2014, Peto_1999, Frank_1998, Risch_2001, Zhang_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000047699	SCV000708438	pathogenic	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294023	SCV001482783	pathogenic	Fanconi anemia, complementation group S	2020-02-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9482581, 24504028, 21324516]
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000047699	SCV002009462	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735450	SCV002043427	pathogenic	Breast and/or ovarian cancer	2021-03-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047699	SCV002047311	pathogenic	not provided	2020-10-07	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in symptomatic individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9482581 (1998), 21324516 (2011), 24504028 (2014), and 26287763 (2015)). Based on the available information, this variant is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000031025	SCV002556886	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-25	criteria provided, single submitter	clinical testing	The BRCA1 c.2071del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) BRCA1:c.2071del is a deletion of a single nucleotide in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 10 of the frame-shift, or 701 (BRCA1 p.(Arg691AspfsTer10):) using NP_009225.1. This is expected to result in disrupted or absent protein product due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun et al., 2018 PMID:30192042). BRCA1:c.2071del (rs80357688) is absent in population databases (gnomAD) and is not on record in FLOSSIES. BRCA1:c.2071del (also described as BRCA1 2190delA using legacy nomenclature) has been reported in multiple unrelated individuals with breast and/or ovarian cancer (Zhang et al., 2011 PMID: 21324516, Cunningham et al., 2014 PMID: 24504028, Ow et al., 2019 PMID: 30875412, George et al., 2021 PMID: 33646313). BRCA1:c.2071del is on record in ClinVar (Variation ID: CD982486) reported by multiple clinical laboratories as pathogenic in association with Hereditary breast and ovarian cancer. This variant is listed in HGMD as ‘disease causing mutation’ in association with Breast cancer (Accession: CD982486).
Revvity Omics, Revvity	RCV000047699	SCV003809701	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031025	SCV004215096	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031025	SCV004818227	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000167861	SCV005399359	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with a risk of breast and ovarian cancer (MIM#604370), fanconi anemia, complementation group S (MIM#617883) and other types of cancer (OMIM). (I). 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance of variants is associated with fanconi anaemia, complementation group S (MIM#617883), whilst autosomal dominant inheritance is associated with an increased risk for familial breast and/or ovarian cancer, 1 (MIM#604370), or pancreatic cancer susceptibility, 4 (MIM#614320). The gene has also been reported to be associated with increased risk for prostate and stomach cancer (PMID: 26236408). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2.1.1 and v3). (SP) 0701 - Other variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. Multiple frameshift and nonsense variants throughout the gene have been reported to be pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. ClinVar: Pathogenic x18 including a submission by an Expert Review panel. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
Sharing Clinical Reports Project (SCRP)	RCV000031025	SCV000053618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031025	SCV000144286	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	RCV000167861	SCV000587182	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000047699	SCV000591365	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Arg691AspfsX10 deletion variant was identified in 7 of 9116 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, or prostate cancer (Castro 2013, Gayther 1999, Jongsma 2002, Risch 2001, Kurian 2008, Zhang 2011). The variant was also identified in dbSNP (ID: rs80357688) “With pathogenic allele”, HGMD, UMD (1X as a causal variant), and the BIC database (24X with clinical importance). The p.Arg691AspfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 691 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000047699	SCV000778764	pathogenic	not provided	2017-05-16	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735450	SCV000863587	pathogenic	Breast and/or ovarian cancer	2009-12-01	no assertion criteria provided	clinical testing