Submissions for variant NM_007294.4(BRCA1):c.5035_5039del (p.Leu1679fs)

dbSNP: rs80357623

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031205	SCV000282336	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	RCV000048742	SCV000076755	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1679Tyrfs*2) 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 a personal and/or family history of breast and ovarian cancer (PMID: 16457150, 17591842). This variant is also known as 5154del5. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031205	SCV000326113	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000483893	SCV000568056	pathogenic	not provided	2018-03-05	criteria provided, single submitter	clinical testing	This deletion of five nucleotides in BRCA1 is denoted c.5035_5039delCTAAT at the cDNA level and p.Leu1679TyrfsX2 (L1679YfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAT[delCTAAT]TACT. The deletion causes a frameshift, which changes a Leucine to a Tyrosine at codon 1679, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.5035_5039delCTAAT, also published as BRCA1 5154del5 using alternate nomenclature, has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Musolino 2005, John 2007, Veschi 2007, Azzollini 2016, Pellegrino 2016). We consider this variant to be pathogenic.
Ambry Genetics	RCV000575406	SCV000660952	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The c.5035_5039delCTAAT pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 5035 to 5039, causing a translational frameshift with a predicted alternate stop codon (p.L1679Yfs*2). Also designated as 5154del5 in some published literature, this alteration has been seen in multiple patients with breast cancer (Musolino A et al. Tumori;91(6):505-12; John EM et al. JAMA 2007 Dec;298(24):2869-76; Cruz-Correa M et al. Hered Cancer Clin Pract 2017 Jan;15:3). 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.
Eurofins Ntd Llc (ga)	RCV000483893	SCV000702500	pathogenic	not provided	2016-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483893	SCV000887708	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575406	SCV000905028	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 16 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID: 16457150, 17591842, 17592676, 18159056, 27062684). 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	RCV000048742	SCV000918793	pathogenic	Hereditary breast ovarian cancer syndrome	2018-11-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5035_5039delCTAAT (p.Leu1679TyrfsX2) 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 (e.g. p.Glu1694X and p.Tyr1703X). The variant was absent in 246172 control chromosomes (gnomAD). c.5035_5039delCTAAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all 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	RCV000048742	SCV000967736	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-19	criteria provided, single submitter	clinical testing	The p.Leu1679TyrfsX2 variant in BRCA1 has been reported in more than 10 individu als with hereditary breast and/or ovarian cancer (HBOC), as well as one young re portedly unaffected individual (<35 years old) with a family history of HBOC (Mu solino 2005, John 2007, Veschi 2007, Azzollini 2016, Breast Information Core (BI C): https://research.nhgri.nih.gov/bic/). This variant was absent from large pop ulation studies. The p.Leu1679TyrfsX2 variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 1679 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (SCV000282336.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal d ominant manner based upon presence in multiple affected individuals, absence fro m the general population, and the predicted impact on the protein. ACMG/AMP Crit eria applied: PVS1, PM2, PS4_Moderate.
Baylor Genetics	RCV000031205	SCV004216898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031205	SCV000053805	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-06-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031205	SCV000145268	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048742	SCV000587445	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research