ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.676del (p.Cys226fs) (rs80357941)

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Total submissions: 16
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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 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 and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the BRCA1 mRNA (c.676delT), causing a frameshift at codon 226. This creates a premature translational stop signal (p.Cys226Valfs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families with breast cancer and ovarian cancer (PMID: 9042907, 22498944, 16287141, 26852130, 22366370, 26745875, 15146557, 24549055). This variant has also been reported as a founder mutation in the Northern Italian population, a common cause of hereditary breast and ovarian cancer in individuals of Northern Italian ancestry (PMID: 26852130). This variant is also known as 795delT or 794delT in the literature. 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 2018-09-07 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000235776 SCV000292504 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.676delT at the cDNA level and p.Cys226ValfsX8 (C226VfsX8) at the protein level. The normal sequence, with the base that is deleted in braces, is TGCT[T]GTGA. The deletion causes a frameshift which changes a Cysteine to a Valine at codon 226, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.676delT, previously published as BRCA1 795delT and 794delT, has been observed in multiple Hereditary Breast/Ovarian Cancer families (Serova 1997, Gorski 2004, Kroiss 2005, Levanat 2012, Maurac 2012, Cini 2016) and has been suggested to be a founder variant from North-East Italy (Cini 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031274 SCV000296393 pathogenic Breast-ovarian cancer, familial 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 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000049091 SCV000591295 pathogenic Hereditary breast and ovarian cancer syndrome 2014-12-02 criteria provided, single submitter clinical testing
Color RCV000129754 SCV000683346 pathogenic Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049091 SCV000699289 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-03 criteria provided, single submitter clinical testing Variant summary: This BRCA1 variant, c.676delT (p.Cys226Valfs) causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "pathogenic." Therefore, the variant of interest has been 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 Hereditary Cancer Syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. This variant was detected in hemizygous state.
Sharing Clinical Reports Project (SCRP) RCV000031274 SCV000053879 pathogenic Breast-ovarian cancer, familial 1 2013-03-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031274 SCV000145663 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031274 SCV000211991 pathogenic Breast-ovarian cancer, familial 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 and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
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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