Submissions for variant NM_007294.4(BRCA1):c.798_799del (p.Ser267fs)

dbSNP: rs80357724

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)	RCV000031279	SCV000282350	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	RCV000167858	SCV000077154	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser267Lysfs*19) 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: 2206311, 7493024, 17221156, 18159056, 18645608, 21324516, 21603858, 23233716, 23289006, 24312913, 25814778, 26010302, 26864382). It is commonly reported in individuals of North Africa including Tunisia, Algeria, and Morocco ancestry (PMID: 2206311, 7493024, 17221156, 18159056, 18645608, 21324516, 21603858, 23233716, 23289006, 24312913, 25814778, 26010302, 26864382). This variant is also known as 917delTT and 916delTT. ClinVar contains an entry for this variant (Variation ID: 37698). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131867	SCV000186922	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The c.798_799delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides between positions 798 and 799, causing a translational frameshift with a predicted alternate stop codon (p.S267Kfs*19). This mutation has previously been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Mahfoudh W et al. Mol. Biol. Rep. 2012 Feb;39(2):1037-46; Laraqui A et al. Int. J. Med. Sci. 2013 Dec;10(1):60-7; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). It was also seen in a pancreatic cancer cohort (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 916delTT 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	RCV000049141	SCV000210004	pathogenic	not provided	2023-07-28	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 individuals with a personal or family history consistent with pathogenic variants in this gene and described as a North African founder variant (Walsh et al., 2011; Uhrhammer et al., 2008; Mahfoudh et al., 2012; Laraqui et al., 2013; De Brakeleer et al., 2015); Not observed 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 917_918delTT; This variant is associated with the following publications: (PMID: 22006311, 31921681, 28776284, 33558524, 7493024, 22684231, 25814778, 18645608, 21324516, 15829246, 22425665, 22460208, 26010302, 26864382, 22866093, 27446417, 28212807, 27225819, 26320393, 25780794, 21603858, 23289006, 28478614, 27062684, 29907814, 30606148, 29506128, 31454914, 31447099, 33084842, 32341426, 30787465, 34290354, 32438681, 34646395, 28888541, 33804961)
Counsyl	RCV000031279	SCV000220420	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-06-17	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000049141	SCV000296319	pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	The BRCA1 c.798_799del (p.Ser267Lysfs*19) 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 multiple individuals and families with breast and/or ovarian cancer and described as a possible North African founder mutation (PMID: 29907814 (2018), 27062684 (2016), 26010302 (2016), 23289006 (2013), 21603858 (2012), 22006311 (2011), 7493024 (1995)). This variant is also reported in an individual with pancreatic cancer (PMID: 29506128 (2018)). 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	RCV000031279	SCV000326412	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506072	SCV000602682	pathogenic	not specified	2016-09-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131867	SCV000683359	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	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 numerous individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 21603858, 23289006, 24312913, 24606420, 25814778, 27062684, 29907814) and is thought to be a founder mutation in the Mediterranean population (PMID: 24312913, 24606420). 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	RCV000167858	SCV000918737	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.798_799delTT (p.Ser267LysfsX19) 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 250012 control chromosomes. c.798_799delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, 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. Eleven clinical diagnostic laboratories and one expert panel (ENIGMA) 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167858	SCV000967733	pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-01	criteria provided, single submitter	clinical testing	The p.Ser267fs variant in BRCA1 has been reported in over 30 individuals with he reditary breast and/or ovarian cancer (HBOC), segregated with disease in one fam ily, and is reported to be a North African founder variant (Laraqui 2013, Mahfou dh 2012, Cherbal 2010, BIC database: https://research.nhgri.nih.gov/bic/). This variant was absent from large population studies. It is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 26 7 and leads to a premature termination codon 19 amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in indiv iduals with HBOC. In addition, this variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235 0.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, presence in multiple affected individuals, and predicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; PS4; PM2.
Mendelics	RCV000031279	SCV001140621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000049141	SCV002020134	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000031279	SCV002104283	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490432	SCV002781388	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-09-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735510	SCV003838908	pathogenic	Breast and/or ovarian cancer	2021-06-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031279	SCV004215061	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802996	SCV004818409	pathogenic	BRCA1-related cancer predisposition	2024-04-25	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 is also known as 917delTT and 916delTT in the literature. This variant has been reported in over 10 individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 17221156, 18159056, 18645608, 20683152, 21603858, 23289006, 24312913, 24606420, 25814778, 27062684, 29907814) and is thought to be a founder mutation in the Mediterranean population (PMID: 24312913, 24606420). 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)	RCV000031279	SCV000053884	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031279	SCV000145687	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	RCV000167858	SCV000587077	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735510	SCV000863648	pathogenic	Breast and/or ovarian cancer	1997-05-22	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001004847	SCV000987228	pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA1 p.Ser267Lysfs is a known pathogenic frameshift variant in exon 11 in a non-functional domain just before the serine-rich domain (A344-507R aa) and many other downstream domains. This null variant (frame-shift) is predicted to encode a truncated non-functional protein, and heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). It is found in a mutational hotspot of 29 pathogenic variants (PM1 Pathogenic Moderate). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235.01) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 56-year- old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.
CZECANCA consortium	RCV000735510	SCV001451788	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000049141	SCV002035049	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000049141	SCV002036324	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031279	SCV002589074	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing