Submissions for variant NM_007294.4(BRCA1):c.2998_3003del (p.Glu1000_Glu1001del)

dbSNP: rs80358333

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048035	SCV000076048	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130154	SCV000184989	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-27	criteria provided, single submitter	clinical testing	The c.2998_3003delGAGGAA variant (also known as p.E1000_E1001del) is located in coding exon 9 of the BRCA1 gene. This variant is an in-frame deletion of 6 nucleotides between nucleotide positions 2998 and 3003 and results in the deletion of 2 glutamate residues at codons 1000 and 1001. This variant was detected in breast and ovarian cancer cohorts (Gaba F et al. Cancers (Basel), 2020 May;12:); Smith SA et al. Gynecol. Oncol. 2001 Dec;83:586-92; Peto J et al. J. Natl. Cancer. Inst. 1999 Jun;91:943-9) but was classified as unknown significance in both publications. Of note, this alteration is also referred to as 3117del6 and "Glu-1000 and Glu-1001 deletion" in published literature. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000656789	SCV000210030	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Located in the critical DNA binding domain (PMID: 15343273); Identified in women with breast or ovarian cancer (PMID: 10359546, 11733976); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3117del6; This variant is associated with the following publications: (PMID: 10359546, 32429029, 31853058, 15343273, 31131967, 11733976)
Pathway Genomics	RCV000111978	SCV000223748	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656789	SCV000600309	uncertain significance	not provided	2021-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130154	SCV000911051	likely benign	Hereditary cancer-predisposing syndrome	2017-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159911	SCV000918713	uncertain significance	not specified	2024-08-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2998_3003delGAGGAA (p.Glu1000_Glu1001del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2998_3003delGAGGAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Peto_1999, Smith_2001, Kang_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 10359546, 11733976, 27375968). ClinVar contains an entry for this variant (Variation ID: 54743). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656789	SCV001473658	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing	The BRCA2 c.2998_3003delGAGGAA; p.Glu1000_Glu1001del variant (rs80358333) is reported in the literature in a cohort individuals affected with early-onset breast cancer (Peto 1999). This variant is found on only five chromosomes (5/282204 alleles) in the Genome Aggregation Database. This variant deletes two moderately conserved glutamate residues, leaving the rest of the protein in-frame. However, due to limited information, the clinical significance of the p.Glu1000_Glu1001del variant is uncertain at this time. References: Peto J et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943-9.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111978	SCV000144603	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2000-06-12	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000111978	SCV000297594	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656789	SCV000591417	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Glu1000_Glu1001del variant has been previously reported in the BIC database as a variant of unknown clinical significance. This is an in frame-deletion which removes two amino acids (Glu-Glu) from the BRCA1 protein. The p.Glu1000 residue is conserved in mammals and the p.Glu1001 residue is not well conserved, with a Gly (glycine) at this position in mouse. However, this information does not help to predict the impact of this variant on protein function. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although this variant is of the type that may have clinical significance. Based on the above information, this variant is classified as a variant of unknown significance.