Submissions for variant NM_007294.4(BRCA1):c.1961dup (p.Tyr655fs)

dbSNP: rs80357522

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031018	SCV000282270	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	RCV000203641	SCV000075674	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr655Valfs*18) 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 (rs80357853, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 7837387, 21324516, 21559243, 22516946, 22970155). This variant is also known as 2080insA. ClinVar contains an entry for this variant (Variation ID: 54417). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130225	SCV000185065	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-29	criteria provided, single submitter	clinical testing	The c.1961dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.Y655Vfs*18). This mutation has been reported in numerous breast, ovarian, or prostate cancer patients (Shattuck-Eidens D et al. JAMA 1995 Feb;273:535-41; Couch FJ et al. Hum. Mutat. 1996;8:8-18; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Leongamornlert D et al. Br. J. Cancer 2012 May;106:1697-701; Couch FJ et al. J Clin Oncol. 2015 Feb 1;33(4):304-11). Of note, this alteration is also designated as 2080insA and c.1945dupA 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.
GeneDx	RCV000047661	SCV000210018	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with personal and/or family history consistent with pathogenic variants in this gene (Shattuck-Eidens 1995, Liede 2002, Alansari 2009, Zhang 2011, Couch 2015, Kim 2019); 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 2080dupA; This variant is associated with the following publications: (PMID: 8807330, 21324516, 27509926, 28559958, 34657373, 29470806, 29339979, 28918466, 29922827, 27157322, 7837387, 22516946, 26010302, 25884701, 25452441, 18340530, 12181777, 21751003, 21559243, 16905680, 26723226, 30702160, 30078507, 28176296, 30720243, 28724667, 29909963, 30678073, 31161121, 30199306, 31528241, 33054725, 32581362, 26577449, 31825140, 32885271, 33758026, 35273153)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047661	SCV000296401	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000098 (3/30596 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer (PMID: 28724667 (2017), 25452441 (2015), 24728189 (2014), 22970155 (2012), 21324516 (2011), 18340530 (2009), 17688236 (2007), 12181777 (2002), 7837387 (1995)), prostate cancer (PMID: 23569316 (2013), 22516946 (2012)), or renal cell carcinoma (RCC) (PMID: 21751003 (2011)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031018	SCV000325203	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031018	SCV000564296	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000203641	SCV000591358	pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130225	SCV000683004	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2080insA and c.1961insA in the literature. 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 observed in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 7837387, 12181777, 17688236, 18340530, 21324516, 22970155, 24728189, 31161121). This variant also has been reported in individuals affected with prostate and renal cell carcinoma (PMID: 21751003, 22516946). This variant has been identified in 3/250730 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203641	SCV000698902	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1961dupA (p.Tyr655ValfsX18) 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 allele was found at a frequency of 1.2e-05 in 250730 control chromosomes. c.1961dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or Prostate Cancer (e.g. Shaltuck-Eidens_1995, Ramus_2007, Song_2014, Zhang_2011, Liede_2002, Leongamornlert_2012, Rebbeck_2018). 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. 12 submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3DMed Clinical Laboratory Inc	RCV000677810	SCV000803969	pathogenic	Ovarian cancer	2018-04-08	criteria provided, single submitter	clinical testing
Academic Department of Medical Genetics, University of Cambridge	RCV000130225	SCV000992226	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000047661	SCV001450388	pathogenic	not provided	2018-01-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031018	SCV004216971	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803964	SCV005428592	pathogenic	BRCA1-related cancer predisposition	2024-07-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2080insA and c.1961insA in the literature. 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 observed in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 7837387, 12181777, 17688236, 18340530, 21324516, 22970155, 24728189, 31161121). This variant also has been reported in individuals affected with prostate and renal cell carcinoma (PMID: 21751003, 22516946). This variant has been identified in 3/250730 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.
Sharing Clinical Reports Project (SCRP)	RCV000031018	SCV000053611	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-07-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031018	SCV000144261	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	RCV000203641	SCV000587175	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735521	SCV000863659	pathogenic	Breast and/or ovarian cancer	2014-01-13	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031018	SCV002589090	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing