ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2998_3003del (p.Glu1000_Glu1001del) (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 and ovarian cancer syndrome 2020-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130154 SCV000184989 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-12 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. T<span style="background-color:initial">hese amino acid positions are well conserved in available vertebrate species. Of note, this alteration is also referred to as 3117del6 and "Glu-1000 and Glu-1001 deletion" in published literature. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000656789 SCV000210030 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing This in-frame deletion of six nucleotides in BRCA1 is denoted c.2998_3003delGAGGAA at the cDNA level and p.Glu1000_Glu1001del (E1000_E1001del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GCTA[delGAGGAA]AACT. This variant, also known as EE1000del using alternative nomenclature, was observed in one individual with early-onset breast cancer unselected for family history (Peto 1999). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion is located in the DNA binding domain and the RAD51 binding region (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 Glu1000_Glu1001del to be a variant of uncertain significance.
Pathway Genomics RCV000111978 SCV000223748 uncertain significance Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159911 SCV000600309 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
Color Health, Inc 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 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2998_3003delGAGGAA (p.Glu1000_Glu1001del) variant is an in-frame deletion in a non-repetitive region. The variant is outside of two well-known BCRT domains. One in silico tool (Mutation Taster) predicts a benign outcome for this variant. This variant was found in 5/246598 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000045 (5/111478). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in multiple affected individuals in literature and clinical databases, however without strong evidence for or against pathogenicity. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287020 SCV001473658 uncertain significance none 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 1 2000-06-12 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000111978 SCV000297594 likely benign Breast-ovarian cancer, familial 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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