ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2293 of the BRCA2 protein (p.Phe2293Leu). This variant is present in population databases (rs80358912, gnomAD 0.06%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12442275, 30262796, 34196900). ClinVar contains an entry for this variant (Variation ID: 52216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 21741379). 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.

The BRCA2 c.6877T>C; p.Phe2293Leu variant (rs80358912) is reported in the literature in several individuals affected with breast cancer (Calderon-Garciduenas 2005, Quezada Urban 2018, Ruiz-Flores 2002). This variant is found in Latino population with an overall allele frequency of 0.05% (17/34230 alleles) in the Genome Aggregation Database. The phenylalanine at codon 2293 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, a peptide containing this variant exhibited apoptotic effects on cultured cells similar to a wildtype peptide (Warren 2002), although the physiological relevance of this assay is uncertain. Due to limited information, the clinical significance of the p.Phe2293Leu variant is uncertain at this time. References: Calderon-Garciduenas AL et al. Clinical follow up of mexican women with early onset of breast cancer and mutations in the BRCA1 and BRCA2 genes. Salud Publica Mex. 2005 Mar-Apr;47(2):110-5. Quezada Urban R et al. Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility. Cancers (Basel). 2018 Sep 27;10(10). Ruiz-Flores P et al. BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico. Hum Mutat. 2002 Dec;20(6):474-5. Warren CR et al. A new assay for functional screening of BRCA2 linker region mutations identifies variants that alter chemoresistance to cisplatin. Exp Cell Res. 2011 Sep 10;317(15):2099-109.

Observed in individuals with a personal or family history of breast cancer (Ruiz-Flores 2002, Quezada Urban 2018); Published functional studies demonstrate no damaging effect: No significant impact on cell growth or cisplatin sensitivity compared to wild type in an in vitro assay (Warren 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as BRCA2 7105T>C; This variant is associated with the following publications: (PMID: 15889636, 12442275, 30262796, 21741379, 31331294)

This missense variant replaces phenylalanine with leucine at codon 2293 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with breast cancer and 1 unaffected individual (PMID: 15889636, 31331294). This variant has been identified in 17/248864 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.

This missense variant replaces phenylalanine with leucine at codon 2293 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with breast cancer and 1 unaffected individual (PMID: 15889636, 31331294). This variant has been identified in 17/248864 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: BRCA2 c.6877T>C (p.Phe2293Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249144 control chromosomes, predominantly at a frequency of 0.0005 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.6877T>C has been reported in the literature in individuals of Mexican descent who were affected with Hereditary Breast and Ovarian Cancer (Ruiz-Flores_2002, Calderon-Garciduenas_2005, Quezada_2018), however without strong evidence for causality (such as co-segregation data). These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant was also found in a healthy control of Latino origin (Zayas-Villanueva_2019). Co-occurrences with other pathogenic variants have been reported (in the BIC database: BRCA1 c.798_799delTT (p.Val266_Ser267ValLysfs); and in an internal LCA sample: BRCA2 c.6078_6079delAA (p.Glu2028fsX20)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function evaluating cell survival and apoptotic index of stably transfected cell lines treated with cisplatin. These results showed no damaging effect of this variant (Warren 2011). The following publications have been ascertained in the context of this evaluation (PMID: 15889636, 30262796, 34196900, 12442275, 21741379, 31331294). ClinVar contains an entry for this variant (Variation ID: 52216). Based on the evidence outlined above, the variant was classified as likely benign.