Submissions for variant NM_007294.4(BRCA1):c.3048_3052dup (p.Asn1018fs)

dbSNP: rs80357856

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019262	SCV000323556	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048059	SCV000076072	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1018Metfs*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 present in population databases (rs80357856, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11781691, 15951958, 20151938, 24504028). It is commonly reported in individuals of Western Swedish ancestry (PMID: 11781691, 15951958, 20151938). This variant is also known as 3171ins5. ClinVar contains an entry for this variant (Variation ID: 54763). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131332	SCV000186306	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	The c.3048_3052dupTGAGA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TGAGA at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.N1018Mfs*8). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families and has been established as a Swedish founder mutation and the most recurrent BRCA1 or BRCA2 mutation in this population (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Johannsson O et al. Am J Hum Genet, 1996 Mar;58:441-50; Einbeigi Z et al. Eur J Cancer, 2001 Oct;37:1904-9; Bergman A et al. Eur. J. Hum. Genet. 2001 Oct;9:787-93; Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Thomassen M et al. Acta Oncol, 2008;47:772-7; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Janavicius R. EPMA J. 2010 Sep;1:397-412; Cunningham JM et al. Sci Rep 2014;4:4026; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Nielsen HR et al. Fam Cancer, 2016 10;15:507-12; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). Of note, this alteration is also referred to as 3171ins5, 3172ins5 and 3166ins5 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	RCV000159913	SCV000210033	pathogenic	not provided	2021-12-27	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 families with breast, ovarian, and/or pancreatic cancers and is the most common Swedish founder variant (Shattuck-Eidens 1995, Johannsson 1996, Bergman 2001, Cunningham 2014); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3171ins5 or 3166ins5; This variant is associated with the following publications: (PMID: 18465347, 18559594, 24504028, 11781691, 8644702, 7837387, 23199084, 26295337, 24728189, 28152038, 27720647, 11576847, 27836010, 30720243, 29339979, 32719484, 31447099)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019262	SCV000325544	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019262	SCV000564330	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131332	SCV000683084	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-03	criteria provided, single submitter	clinical testing	This variant inserts 5 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 3166ins5, 3171ins5, and 3172ins5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 7837387, 8644702, 11576847, 11781691, 15951958, 18465347, 18559594, 20104584, 20151938, 24504028, 34680387). This variant has been identified recurrently in the Swedish population and has been established as a founder variant (PMID: 8644702, 11576847, 11781691, 15951958, 20151938, 23199084). This variant has been identified in 90 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/251144 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159913	SCV000887657	pathogenic	not provided	2021-09-30	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159913	SCV001450244	pathogenic	not provided	2014-08-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159913	SCV002551008	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159913	SCV003810344	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000019262	SCV004215163	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000019262	SCV004815612	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-26	criteria provided, single submitter	clinical testing	This variant inserts 5 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 3166ins5, 3171ins5, and 3172ins5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 7837387, 8644702, 11576847, 11781691, 15951958, 18465347, 18559594, 20104584, 20151938, 24504028, 34680387). This variant has been identified recurrently in the Swedish population and has been established as a founder variant (PMID: 8644702, 11576847, 11781691, 15951958, 20151938, 23199084). This variant has been identified in 90 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/251144 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048059	SCV004848367	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Asn1018MetfsX8 variant in BRCA1 has been reported in >40 Caucasian individuals with BRCA1-associated cancers and segregated with disease in > 15 affected relatives (initial description by Shattuck-Eidens 1995 PMID: 7837387). It has also been identified in 0.004% (4/113524) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 10/18/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 54763). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1018 and leads to a premature termination codon 8 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 HBOC. This variant has been characterized by haplotype mapping as a founder mutation in western Sweden, accounting for a majority of BRCA1 variants identified in the region (Bergman 2005 PMID: 15951958). Additional variants involving this codon (c.3052_3053ins5; c.3049_3050ins7; c.3049G>T, p.Glu1017Ter) have been identified in individuals with HBOC and are classified as pathogenic by ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PVS1, PM2, PS4, PP1_Strong.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000019262	SCV005045928	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048059	SCV005184838	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3048_3052dupTGAGA (p.Asn1018MetfsX8) 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. The variant allele was found at a frequency of 1.6e-05 in 254200 control chromosomes. c.3048_3052dupTGAGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 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. The following publications have been ascertained in the context of this evaluation (PMID: , 18465347, 24728189, 7837387, 24240112). ClinVar contains an entry for this variant (Variation ID: 54763). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000159913	SCV005198084	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing
OMIM	RCV000019262	SCV000039550	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2001-10-01	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019262	SCV000144624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000019262	SCV000189891	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048059	SCV000587274	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353931	SCV000591422	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn1018MetfsX8 variant was identified in the literature in 6 of 1714 proband chromosomes (frequency: 0.003) from individuals or families with Breast and Ovarian cancers (Hakansson 1997, Thomassen 2008, Kainu 1996, Bergman 2001). The variant was identified in dbSNP (ID: rs80357856) “With pathogenic allele”. In the Exome Aggregation Consortium (ExAC) database the variant was identified in 4 of 66706 European (Non-Finnish) alleles (frequency 6 x 10-5.) The variant was also identified in LOVD 2x classified as pathogenic; the ClinVar database (classified as a pathogenic variant by Ambry Genetics, GeneDx, Pathway Genetics, OMIM, Invitae and BIC); in the BIC database (46x with clinical importance, class 5 definitely pathogenic); in UMD (1x as a class 5 causal variant). In Clinvitae the variant was identified 5x as pathogenic The c.3048_3052dupTGAGA variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Asn1018MetfsX8 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1018 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.
BRCAlab, Lund University	RCV000019262	SCV002589102	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing