ClinVar Miner

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

dbSNP: rs80358333
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048035 SCV000076048 likely benign Hereditary breast ovarian cancer syndrome 2023-10-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130154 SCV000184989 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-22 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. These amino acid positions are 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000656789 SCV000210030 uncertain significance not provided 2022-09-26 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; Not observed at significant frequency in large population cohorts (gnomAD); Located in the critical DNA binding domain (Narod and Foulkes, 2004); Identified in women with breast or ovarian cancer (Peto et al. 1999; Smith et al., 2001); Also known as 3117del6; This variant is associated with the following publications: (PMID: 10359546, 31131967, 15343273, 32429029, 31853058, 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 2023-08-08 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). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: two submitters classified the variant as likely benign while four classified the variant as VUS. 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.

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