ClinVar Miner

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

dbSNP: rs80357941
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Total submissions: 19
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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.
Invitae RCV000049091 SCV000077104 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-18 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 2021-10-05 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 RCV000031274 SCV000296393 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
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
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

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