Hereditary variants of unknown significance in African American women with breast cancer

Abstract

Expanded implementation of genetic sequencing has precipitously increased the discovery of germline and somatic variants. The direct benefit of identifying variants in actionable genes may lead to risk reduction strategies such as increased surveillance, prophylactic surgery, as well as lifestyle modifications to reduce morbidity and mortality. However, patients with African ancestry are more likely to receive inconclusive genetic testing results due to an increased number of variants of unknown significance decreasing the utility and impact on disease management and prevention. This study examines whole exome sequencing results from germline DNA samples in African American women with a family history of cancer including 37 cases that were diagnosed with breast cancer and 51 family members. Self-identified ancestry was validated and compared to the 1000 genomes population. The analysis of sequencing results was limited to 85 genes from three clinically available common genetic screening platforms. This target region had a total of 993 variants of which 6 (<1%) were pathogenic or likely pathogenic, 736 (74.1%) were benign, and 170 (17.1%) were classified as a variant of unknown significance. There was an average of 3.4±1.8 variants with an unknown significance per individual and 85 of 88 individuals (96.6%) harbored at least one of these in the targeted genes. Pathogenic or likely pathogenic variants were only found in 6 individuals for the BRCA1 (p.R1726fs, rs80357867), BRCA2 (p.K589fs, rs397507606 & p.L2805fs, rs397507402), RAD50 (p.E995fs, rs587780154), ATM (p.V2424G, rs28904921), or MUTYH (p.G396D, rs36053993) genes. Strategies to functionally validate the remaining variants of unknown significance, especially in understudied and hereditary cancer populations, are greatly needed to increase the clinical utility and utilization of clinical genetic screening platforms to reduce cancer incidence and mortality.

Whole‐exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways

“…Non-European populations are known to have higher VUS rates. 48,49 These gaps, coupled with the poorly understood pathophysiology of BPH, increase the need for studies into disparately impacted patient groups. CABP1 is a calcium-binding protein that shares similarities with calmodulin.…”

“…These genes are not currently annotated in ClinVar, meaning they are variants of unknown significance (VUS). Non‐European populations are known to have higher VUS rates 48,49 . These gaps, coupled with the poorly understood pathophysiology of BPH, increase the need for studies into disparately impacted patient groups.…”

Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022

“…Previous studies have been hampered by small sample sizes. 15,16,[23][24][25][26][27][28][29][30][31][32][33][34] Other studies have focused on a limited set of genes, such as BRCA1 and BRCA2, 25,26,35 although there are an array of high-and moderate-risk hereditary cancer genes for which clinical management strategies have been developed. [36][37][38] Lack of sufficient data from AA/B individuals for genes such as ATM, CHEK2, and PALB2 may impair risk estimation, genetic counseling, and use of precision medicine approaches.…”