Submissions for variant NM_007294.4(BRCA1):c.2411_2412del (p.Gln804fs)

dbSNP: rs80357664

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031047	SCV000282279	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	RCV000047829	SCV000075842	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln804Leufs*5) 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 and/or ovarian cancer (PMID: 10667595, 16168118, 18489799, 25777348, 26681312). This variant is also known as 2530delAG. ClinVar contains an entry for this variant (Variation ID: 37466). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131426	SCV000186407	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	The c.2411_2412delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2411 to 2412, causing a translational frameshift with a predicted alternate stop codon (p.Q804Lfs*5). This mutation has been reported in numerous breast and/or ovarian cancer families to date (Rothfuss A et al. Cancer Res. 2000 Jan 15;60(2):390-4; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7(5):R728-36; Pal T et al. Cancer. 2005 Dec;104(12):2807-16; Weber F et al. Am. J. Hum. Genet. 2006 Jun;78(6):961-72; Dworkin AM et al. Fam. Cancer. 2009 Apr;8(4):339-46; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Bhaskaran SP et al. Int J Cancer. 2019 08;145:962-973; Hoyer J et al. BMC Cancer. 2018 Sep;18:926). Of note, this alteration is also designated as 2530delAG in the published literature. This variant was not reported in population-based 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	RCV000159906	SCV000210023	pathogenic	not provided	2023-11-19	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2530_2531del; This variant is associated with the following publications: (PMID: 24094589, 25452441, 18474296, 26681312, 16685647, 30257646, 28888541, 16168118, 10667592, 18489799, 16284991, 28324225, 28152038, 19147582, 19340607, 25400221, 18824701, 32719484, 32885271, 30702160, 33151324, 32295079, 31825140, 31853058, 35409996)
GeneKor MSA	RCV000159906	SCV000296767	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This is a deletion of 2 base pairs, which results in frameshift and creation of a stop codon 5 amino acid residues later. It is expected to result in a truncated, non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant has been also described in mutation databases as 2530delAG.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031047	SCV000325348	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000458659	SCV000540951	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159906	SCV000600287	pathogenic	not provided	2016-09-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131426	SCV000683033	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant deletes 2 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 been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11802209, 12566964, 16168118, 16284991, 16685647, 18489799, 19147582, 19340607, 25452441, 25777348, 26681312, 28324225, 30257646, 30702160), and has been identified in 54 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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	RCV000047829	SCV000698948	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2411_2412delAG (p.Gln804LeufsX5) 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 250542 control chromosomes (gnomAD). c.2411_2412delAG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Couch_2015, Pal_2005, Pohlreich_2003, Weber_2006, Susswein_2016). 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) and one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000159906	SCV000806914	pathogenic	not provided	2017-09-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159906	SCV001249205	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159906	SCV001448109	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159906	SCV002009459	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000031047	SCV002556905	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-10-08	criteria provided, single submitter	clinical testing	The BRCA1 c.2411_2412delAG variant is classified as Pathogenic
MGZ Medical Genetics Center	RCV000031047	SCV002580365	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-08-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031047	SCV004100799	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PS4_SUP,PM2_SUP
Baylor Genetics	RCV000031047	SCV004215167	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000458659	SCV004242420	pathogenic	Familial cancer of breast	2024-01-12	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
All of Us Research Program, National Institutes of Health	RCV000031047	SCV004818183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-19	criteria provided, single submitter	clinical testing	This variant deletes 2 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 been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11802209, 12566964, 16168118, 16284991, 16685647, 18489799, 19147582, 19340607, 25452441, 25777348, 26681312, 28324225, 30257646, 30702160), and has been identified in 54 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031047	SCV000053641	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031047	SCV000144421	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	RCV000047829	SCV000587213	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001270971	SCV001451776	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356861	SCV001552134	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The BRCA1 p.Gln804Leufs*5 variant was identified in 7 of 24906 proband chromosomes (frequency: 0.0003) from individuals or families with breast or ovarian cancer (Couch 2015, Machackova 2008, Pal 2005, Pohlreich 2005, Susswein 2015). The variant was also identified in dbSNP (ID: rs80357664) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and eleven other submitters), COGR , LOVD 3.0 (15x pathogenic), UMD-LSDB (4x as causal), BIC Database (14x as clinically important), and in ARUP Laboratories ( definitely pathogenic), databases. The variant was not identified in Cosmic, or Zhejiang University, databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln804Leufs*5 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 804 and leads to a premature stop codon at position 808. 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 breast or 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.
CZECANCA consortium	RCV001391197	SCV001593140	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
CZECANCA consortium	RCV001356861	SCV003804345	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing