ClinVar Genomic variation as it relates to human health

This variant, c.644_646del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Glu215del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746887088, gnomAD 0.006%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27257965, 30262796, 35402282). This variant has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. This variant is also known as p.E213del and c.640_642del. ClinVar contains an entry for this variant (Variation ID: 52106). 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.

This variant, in exon 8 of the BRCA2 gene, is denoted c.644_646delAAG at the DNA level or p.Glu215del (E215del) at the protein level. The normal sequence with the bases that are deleted in braces is: TGAAG{delAAG}CATCT. This in frame deletion of 3 base pairs results in the loss of a single Glutamic acid residue at a position that is well conserved throughout evolution, however, it is not located in a known functional domain. BRCA2 c.644_646delAAG has not, to our knowledge, been reported as a mutation or as a benign polymorphism. It has been reported in the Breast Cancer Information Core (BIC) database with unknown clinical importance. Since in frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time. Based on currently available information, we consider BRCA2 c.644_646delAAG to be a variant of unknown significance. The variant is found in BRCA1-BRCA2 panel(s).

This variant causes the in-frame deletion of a single amino acid, glutamic acid 215, in the BRCA2 protein. This variant is also known as c.640_642del in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 27257965, 30262796, 35402282, 36601340). This variant has been identified in 2/244584 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.

The c.644_646delAAG variant (also known as p.E215del) is located in coding exon 7 of the BRCA2 gene. This variant results from an in-frame AAG deletion at nucleotide positions 644 to 646. This results in the in-frame deletion of a glutamic acid at codon 215. This alteration has been reported in several individuals with a history of breast and/or ovarian cancer (Zhong X. et al. PLoS One. 2016 Jun;11(6):e0156789; Quezada Urban R. et al. Cancers (Basel). 2018 Sep;10(10); Abdel-Razeq H. et al. Front Oncol. 2022 Mar;12:673094). 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.

Variant summary: BRCA2 c.644_646delAAG (p.Glu215del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 8.2e-06 in 244584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.644_646delAAG has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Abdel-Rezeq_2020, Quezada Urban_2018, Zhong_2016) without strong evidence for causality. 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: 19941162, 35402282, 30262796, 27257965). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant causes an in-frame deletion of one amino acid in the BRCA2 protein. In the published literature, the variant has been reported in individuals with breast cancer or with suspected hereditary breast/ovarian cancer (PMIDs: 35402282 (2022), 30262796 (2018), and 27257965 (2016)). In addition, this variant has been reported in the somatic state in a patient with uterine leiomyosarcoma (PMID: 35454841 (2022)). The frequency of this variant in the general population, 0.0000082 (2/244584 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.