Submissions for variant NM_007294.4(BRCA1):c.4035del (p.Glu1346fs)

dbSNP: rs80357711

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031141	SCV000282321	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.
Invitae	RCV000048413	SCV000076426	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1346Lysfs*20) 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 (rs80357711, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15591272, 20345474, 20569256, 22032251, 23199084). This variant is also known as 4153delA and 4154delA. ClinVar contains an entry for this variant (Variation ID: 37560). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074587	SCV000108672	pathogenic	not provided	2022-01-17	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 is reported as a pathogenic founder variant in several eastern European countries (Gayther 1996, Bogdanova 2010, Janavicius 2013, Szwiec 2015, Synowiec 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4153delA or 4154delA; This variant is associated with the following publications: (PMID: 29684080, 29339979, 8644703, 26779294, 23274591, 26928677, 29492181, 28166811, 23149842, 22032251, 22009639, 20345474, 20507347, 20569256, 24504028, 24797986, 20223023, 24528374, 26753012, 26843898, 27836010, 26681312, 29723101, 28831036, 29719582, 29785153, 29086229, 28279176, 30720243, 30322717, 31159747, 29625052, 26689913, 27535533)
Ambry Genetics	RCV000130638	SCV000185517	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The c.4035delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4035, causing a translational frameshift with a predicted alternate stop codon (p.E1346Kfs*20). This mutation has been reported in numerous cases of breast and ovarian cancer (Gayther SA et al. Am. J. Hum. Genet. 1996 Mar;58:451-6; Elsakov P et al. Clin. Genet. 2010 Oct;78:373-6; Uglanitsa N et al. Clin. Genet. 2010 Oct;78:377-80; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Maxwell KN et al. Nat. Commun. 2017 08;8:319; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Yehia L et al. PLoS Genet., 2018 04;14:e1007352; Kowalik A et al. PLoS ONE, 2018 Jul;13:e0201086; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165). Furthermore, this mutation is regarded as a founder mutation of Baltic origin, with the highest observed frequency in Lithuania (Janavicius R et al. Eur. J. Med. Genet. 2013 Mar;56:125-30). Of note, this alteration is also designated as 4154delA and 4153delA 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.
Counsyl	RCV000031141	SCV000221052	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-01-19	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074587	SCV000296398	pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
GeneKor MSA	RCV000239274	SCV000296800	pathogenic	Familial cancer of breast	2021-01-09	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 11 of the BRCA1 mRNA (c.4035delA), causing a frameshift after codon 1346 and the creation of a premature translational stop signal 20 amino acid residues later (p.Glu1346Lysfs*20) This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This variant is also known as 4153delA and 4154delA in the international literature and is a known common cause of breast and ovarian cancer in individuals from Eastern Europe (PMID: 22032251 ,23199084).This mutation has been described in the mutation database ClinVar (Variation ID: 37560).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031141	SCV000325817	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031141	SCV000564320	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000048413	SCV000588051	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048413	SCV000605754	pathogenic	Hereditary breast ovarian cancer syndrome	2019-07-26	criteria provided, single submitter	clinical testing	The p.Glu1346LysfsX20 variant in BRCA1 has been reported in >100 individuals with BRCA1-associated cancers and is a known eastern European founder mutation (Janavicius 2013, Tihomirova 2014, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has been identified in 12/129020 (0.009%) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 20 amino acids downstream. This alteration 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 individuals with HBOC. Morevoer, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282321.1). In summary, the p.Glu1346LysfsX20 variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4.
Color Diagnostics, LLC DBA Color Health	RCV000130638	SCV000683145	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4153delA and 4154delA in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with breast and ovarian cancer (PMID: 20345474, 24770866, 29785153, 30040829) and is known to be a founder mutation in the Baltic Population (PMID: 23274591). This variant also has been detected in a breast cancer case-control meta-analysis in 11/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000791). This variant has been identified in 12/282514 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048413	SCV000699099	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4035delA (p.Glu1346LysfsX20) 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 allele was found at a frequency of 2.8e-05 in 253150 control chromosomes. c.4035delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Gorski_2004, Bogdanova_2010, 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. 21 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031141	SCV000993554	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-02-04	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000074587	SCV001247351	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PS4:Moderate
Institute of Genomics, University of Tartu	RCV000031141	SCV001430692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074587	SCV001447897	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000074587	SCV001449606	pathogenic	not provided	2015-03-06	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031141	SCV001499714	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	RCV000074587	SCV002009408	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074587	SCV002049950	pathogenic	not provided	2021-11-26	criteria provided, single submitter	clinical testing	The BRCA1 c.4035delA; p.Glu1346LysfsTer20 variant (rs80357711), also known as 4153del or 4154del, is reported in several individuals affected with breast and ovarian cancer and is described as a pathogenic founder variant in the European population (Bogdanova 2010, Elsakov 2010, Plakhins 2011). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37560) and is listed in the non-Finnish European population with an allele frequency of 0.009% (12/129,020 alleles) in the Genome Aggregation Database. 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: Bogdanova NV et al. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet. 2010 Oct;78(4):364-72. PMID: 20569256. Elsakov P et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010 Oct;78(4):373-6. PMID: 20345474. Plakhins G et al. Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia. BMC Med Genet. 2011 Oct 27;12:147. PMID: 22032251.
MGZ Medical Genetics Center	RCV000031141	SCV002581449	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000074587	SCV002760930	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000239274	SCV003804717	pathogenic	Familial cancer of breast	2023-01-20	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
Revvity Omics, Revvity	RCV000074587	SCV003811700	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031141	SCV004176014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM5_STR
Baylor Genetics	RCV000031141	SCV004212672	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000031141	SCV000039547	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1996-03-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031141	SCV000053740	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-04-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031141	SCV000144938	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	RCV000048413	SCV000587366	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031141	SCV000591480	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Glu1346LysfsX20 deletion variant was identified in 176 of 22934 proband chromosomes (frequency: 0.008) from individuals with prostate cancer, breast cancer, ovarian cancer, or other gynaecological tumours, and was present in 3 of 11336 control chromosomes (frequency: 0.0003) (Bayraktar 2012, Bogdanova 2010, Cybulski 2013, Elsakov 2010, Gayther 1996 8644703, Jakubowska 2008, Plakhins 2011, Tikhomirova 2005, Uglanitsa 2010). The variant is described in the literature as a founder mutation in Slavic and Baltic countries, including Poland, Belarus, Latvia, Russia, and Lithuania (Bogdanova 2010, Cybulski 2013, Elsakov 2010, Ozolina 2009, Uglanitsa 2010). The variant was also identified in dbSNP (ID: rs80357711) “With pathogenic allele”, HGMD, UMD (2X as a causal variant), and the BIC database (51X as a variant with clinical importance). The p.Glu1346LysfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1346 and leads to a premature stop codon 20 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.
CZECANCA consortium	RCV001271017	SCV001451830	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031141	SCV002588803	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing