Submissions for variant NM_007294.4(BRCA1):c.843_846del (p.Ser282fs)

dbSNP: rs80357919

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019253	SCV000299490	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	RCV000049168	SCV000077181	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17683). This variant is also known as 962del4. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9663595, 10196379, 17319787, 21203900, 21324156, 23110154). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser282Tyrfs*15) 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).
Ambry Genetics	RCV000131872	SCV000186927	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The c.843_846delCTCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of four nucleotides at positions 843 to 846, causing a translational frameshift with a predicted alternate stop codon (p.S282Yfs*15). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Janezic SA et al. Hum. Mol. Genet. 1999;8:889-97; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Wagner TM et al. Int. J. Cancer. 1998 July;77:354-60; Tihomirova L et al. Adv Med Sci. 2014 Mar;59:114-9; Pern F et al. PLoS ONE. 2012 Oct;7:e47993; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Dobricic J et al. J. Hum. Genet. 2013 Aug;58:501-7; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this mutation is also designated as 962del4 in published 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	RCV000412670	SCV000210005	pathogenic	not provided	2021-01-05	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; Reported in numerous individuals with personal and/or family histories of breast and/or ovarian cancer (Wagner 1998, Janezic 1999, Stegel 2011, Zhang 2011, Pern 2012, Song 2014, Muendlein 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 962del4 and 962_965delCTCA; This variant is associated with the following publications: (PMID: 10196379, 9663595, 21324516, 23110154, 22366370, 21232165, 23397983, 23635950, 24797986, 24728189, 27221827, 25971625, 27533253, 26306726, 25066507, 18489799, 11179017, 27062684, 29339979, 28324225, 31159747, 32341426, 26681312)
GeneKor MSA	RCV000412670	SCV000296764	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 282 and the creation of a premature translation stop signal 15 amino acid residues later- p.(Ser282Tyrfs). This is expected to result in an absent or disrupted protein product.Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747).This mutation has been described in the mutation database ClinVar (Variation ID: 17683).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019253	SCV000326442	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019253	SCV000564365	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000412670	SCV000600442	pathogenic	not provided	2017-03-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131872	SCV000683371	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides 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 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	RCV000049168	SCV000699318	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.843_846delCTCA (p.Ser282TyrfsX15) 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 254112 control chromosomes (gnomAD and publication data). c.843_846delCTCA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Wagner_1998, Janezic_1999, Judkins_2005, Song_2014, 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. Twelve ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000412670	SCV001447448	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000019253	SCV001499627	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000412670	SCV002009405	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000019253	SCV002580575	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000019253	SCV002762794	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR, PM2_SUP
Fulgent Genetics, Fulgent Genetics	RCV002496415	SCV002810445	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-07-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019253	SCV003921010	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-03	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Baylor Genetics	RCV000019253	SCV004215063	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003992160	SCV004812085	pathogenic	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000049168	SCV004848361	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Ser282TyrfsX15 variant in BRCA1 has been reported in 23 individuals with BRCA1-related cancers (first published by Wagner 1998 PMID: 9663595). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17683). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 282 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000019253	SCV005045949	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000412670	SCV005090362	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000412670	SCV005198295	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV000412670	SCV005328464	pathogenic	not provided	2024-08-23	criteria provided, single submitter	clinical testing
OMIM	RCV000019253	SCV000039541	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-05-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019253	SCV000109435	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-05-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019253	SCV000145702	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	RCV000049168	SCV000587080	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000412670	SCV000591305	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Ser282TyrfsX15 variant has been reported in 25 of 3463 probands with breast or ovarian cancer (Anton-Culver_2000_10882857, Capalbo_2006_16760289, Wagner_1998_9663595, Zhang_2011_21324516, Machackova_2008_18489799, Janezic_1999_10196379, http://research.nhgri.nih.gov/bic/). In addition, The p.Ser282TyrfsX15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 282 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the BRCA1 gene, which makes it highly likely that the p.Ser282TyrfsX15 variant is pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019253	SCV000733664	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735511	SCV000863649	pathogenic	Breast and/or ovarian cancer	2000-08-01	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000735511	SCV001451789	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000412670	SCV001905698	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000412670	SCV001965266	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019253	SCV004244143	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000019253	SCV005061276	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control