Submissions for variant NM_007294.4(BRCA1):c.676del (p.Cys226fs)

dbSNP: rs80357941

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031274	SCV000299473	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	RCV000049091	SCV000077104	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys226Valfs*8) 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 cancer and ovarian cancer (PMID: 9042907, 15146557, 16287141, 22366370, 22498944, 24549055, 26745875, 26852130). It is commonly reported in individuals of Northern Italian ancestry (PMID: 26852130). This variant is also known as 795delT or 794delT. ClinVar contains an entry for this variant (Variation ID: 37693). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129754	SCV000184561	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-11	criteria provided, single submitter	clinical testing	The c.676delT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 676, causing a translational frameshift with a predicted alternate stop codon (p.C226Vfs*8). This pathogenic mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Serova OM et al. Am. J. Hum. Genet. 1997 Mar;60:486-95; Adem C et al. Cancer. 2003 Jan;97:1-11; Miolo G et al. BMC Cancer. 2009 Oct;9:360; Maurac I et al. Int. J. Gynecol. Pathol. 2012 May;31:264-71; Azzollini J et al. Eur J Intern Med. 2016 Jul;32:65-71; Cini G et al. BMC Med. Genet. 2016 Feb;17:11; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also designated as 795delT 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	RCV000235776	SCV000292504	pathogenic	not provided	2022-01-13	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; Observed in multiple Hereditary Breast/Ovarian Cancer families and has been suggested to be a founder variant from North-East Italy (Serova 1997, Gorski 2004, Kroiss 2005, Levanat 2012, Maurac 2012, Cini 2016, Kluz 2018); 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 795delT; This variant is associated with the following publications: (PMID: 15146557, 22366370, 22984553, 9042907, 22498944, 26852130, 16287141, 26843898, 26745875, 28715532, 24549055, 12491499, 16528604, 32719484, 30787465, 32132887, 33478551, 31409081, 29492181, 30441849, 27062684)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235776	SCV000296393	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	The BRCA1 c.676del (p.Cys226Valfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in several affected individuals with breast and/or ovarian cancer (PMIDs: 9042907 (1997), 15146557 (2004), 16287141 (2005), 19818148 (2009), 22366370 (2012), 24549055 (2014), 26745875 (2016), 26852130 (2016), 33888336 (2021), and 35382848 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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	RCV000031274	SCV000326388	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129754	SCV000683346	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-31	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least fifteen individuals and additional families affected with breast and/or ovarian cancer (PMID: 9042907, 12491499, 15146557, 19818148, 22366370, 23772696, 24549055, 26745875, 26852130, 33670479), and haplotype analysis suggests that this may be a founder mutation in hereditary breast and ovarian cancer families of Italian ancestry (PMID: 26852130). 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	RCV000049091	SCV000699289	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.676delT (p.Cys226ValfsX8) 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 242894 control chromosomes. c.676delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Judkins_2005, Gorski_2004, Serova_1997). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002663	SCV001160649	pathogenic	not specified	2019-07-01	criteria provided, single submitter	clinical testing	The BRCA1 c.676delT; p.Cys226fs variant (rs80357941), also known as 795delT or 794delT, is reported in the literature in numerous individuals with a personal or family history of breast and/or ovarian cancer (Azzollini 2016, Cini 2016, Gorski 2004, Kluz 2018, Levanat 2012, Serova 1997, Singer 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37693). Haplotype analysis indicates this variant may be a founder variant in northeastern Italy (Cini 2016). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Azzollini J et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. Cini G et al. Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy. BMC Med Genet. 2016 Feb 6;17:11. Gorski B et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer. 2004 Jul 10;110(5):683-6. Kluz T et al. Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland. Hered Cancer Clin Pract. 2018 Feb 27;16:6. Levanat S et al. Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia. Gene. 2012 May 1;498(2):169-76. Serova OM et al. Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997 Mar;60(3):486-95. Singer CF et al. Clinical implications of genetic testing for BRCA1 and BRCA2 mutations in Austria. Clin Genet. 2014 Jan;85(1):72-5.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199276	SCV001370353	pathogenic	Familial cancer of breast	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031274	SCV001499628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129754	SCV002537888	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	curation
Baylor Genetics	RCV000031274	SCV004217016	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-14	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000235776	SCV005199755	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000031274	SCV005374881	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-10-18	criteria provided, single submitter	clinical testing	PVS1, PM5_Strong, PP4_Moderate
Sharing Clinical Reports Project (SCRP)	RCV000031274	SCV000053879	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031274	SCV000145663	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031274	SCV000211991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000049091	SCV000587070	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353776	SCV000591295	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Cys226ValfsX8 variant was identified in 8 of 1326 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer, and was not identified in 242 control chromosomes from healthy individuals (Adem 2003, Maurac 2012, Miolo 2009, Serova 1997, Singer 2014). The variant was also identified in dbSNP (ID: rs80357941) “With Pathogenic allele, ClinVar database (submitted by Sharing Clinical Reports Project; classified as pathogenic (derived from Myriad reports)), the BIC database (16X with clinical importance), and UMD (2X as a causal variant). In a study by Maurac (2012), a patient with the variant showed loss of heterozygosity of the wildtype allele and presence of the mutated allele in tumour tissue. The p.Cys226ValfsX8 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 226 and leads to a premature stop codon 8 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735463	SCV000863600	pathogenic	Breast and/or ovarian cancer	2014-05-05	no assertion criteria provided	clinical testing