Submissions for variant NM_000059.4(BRCA2):c.7420GAA[2] (p.Glu2476del)

dbSNP: rs876659222

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216655	SCV000275445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The c.7426_7428delGAA variant (also known as p.E2476del) is located in coding exon 13 of the BRCA2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 7426 to 7428. This results in the in-frame deletion of a glutamic acid at codon 2476. This alteration was identified in one proband from a cohort of Argentine cohort of 940 families with breast and/or ovarian cancer (Solano AR et al. Oncotarget, 2017 Sep;8:60487-60495) and in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (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	RCV000766429	SCV000279937	uncertain significance	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This in-frame deletion of 3 nucleotides in BRCA2 is denoted c.7426_7428delGAA at the cDNA level and p.Glu2476del (E2476del) at the protein level. Using alternate nomenclature, this variant may be defined as BRCA2 7654_7656delGAA. The normal sequence, with the bases that are deleted in braces, is AGAA[GAA]CCTT. This deletion of a single Glutamic Acid residue occurs at a position that is not conserved and is located in the FANCD2 binding domain (UniProt). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. 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 BRCA2 Glu2476del to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766429	SCV000600747	uncertain significance	not provided	2024-01-09	criteria provided, single submitter	clinical testing	The BRCA2 c.7426_7428del (p.Glu2476del) variant has been reported in the published literature in affected individuals with breast cancer (PMIDs: 27463008 (2016), 28947987 (2017), 35264596 (2022), and 35534704 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282382 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000216655	SCV000683869	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This variant cause an in-frame deletion of one amino acid, glutamic acid 2476, in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 28947987; Color internal data) and an individual affected with pancreatic cancer (PMID: 25479140). This variant has been identified in 2/282382 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000709330	SCV000838852	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709330	SCV000939150	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-05	criteria provided, single submitter	clinical testing	This variant, c.7426_7428del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Glu2476del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757707698, gnomAD 0.004%). This variant has been observed in individual(s) with breast cancer (PMID: 27463008, 28947987, 35264596, 35534704). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000709330	SCV001737419	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-04-15	criteria provided, single submitter	clinical testing	The BRCA2 c.7426_7428del (p.Glu2476del) change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/13-32929409-TGAA-T?dataset=gnomad_r2_1). It is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). The change results in the deletion of a single glutamic acid residue in the FANCD2 binding domain (PM4). This variant has been reported in an individual with early-onset breast cancer (PMID: 28947987). To our knowledge, functional studies have not been performed for this variant. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PM4.
Fulgent Genetics, Fulgent Genetics	RCV002503870	SCV002797544	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-07-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454632	SCV004186069	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003462468	SCV004213641	uncertain significance	Familial cancer of breast	2024-02-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219956	SCV005395000	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7426_7428delGAA (p.Glu2476del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250980 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7426_7428delGAA has been reported in the literature in individuals affected with breast cancer and pancreatic cancer (eg., Grant_2015, Guindalini_2022, Solano_2017, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported in a patient with breast cancer (BRCA1 c.5074+2T>C), providing supporting evidence for a benign role (e.g., de Oliveira_2022). 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: 25479140, 35264596, 28947987, 35534704). ClinVar contains an entry for this variant (Variation ID: 231555). Based on the evidence outlined above, the variant was classified as uncertain significance.