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Frequency of Mutations in Moderate Penetrance Breast Cancer Genes NBN and ATM in an Unselected Carrier Screening Population

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 Frequency of mutations in moderate penetrance breast cancer: Genes NBN and ATM identified through expanded carrier screening


ATM and NBN have been described as moderate risk breast cancer genes. There is limited published data on the frequency of pathogenic mutations in these genes in the general population.

ATM and NBN are often included in expanded carrier screening (ECS) due to their association with recessive disease. 

• We analyzed Counsyl’s laboratory experience from over 100,000 patients who underwent ECS using next generation sequencing (NGS) to examine the frequency of pathogenic mutations in ATM and NBN in a population unselected for personal or family history of cancer. 



• Individuals were tested for carrier status in up to 108 genes by NGS.

• Variants identified by NGS were curated for recessive disease based on ACMG guidelines. Pathogenic and likely pathogenic variants were included in this analysis.

• Carrier frequencies for the ATM and NBN genes were computed from de-identified aggregate data, tabulated by ethnic group, weighted by US Census Data 2010, and summated to represent the ethnic distribution in the USA. 



Carrier frequencies are derived from 100,434 patients who underwent ECS with an indicated purpose of “routine carrier screening”. Individual carrier frequencies by ethnicity are detailed below.

Cancer screening management guidelines for NBN are based on the well-described Slavic founder mutation c.657_661del5; however, we observe that this mutation accounts for only 31.8% of NBN positives in this population.⁵

The c.7271T>G (V2424G) dominant-negative missense mutation, which has been reported to cause the highest cancer risk in ATM carriers, was found to account for 2.4% of all pathogenic mutations in ATM.⁵ 



• We estimate pathogenic mutations in ATM occur in approximately 1/270 individuals in the US population. A well-described missense mutation causing the highest reported risk for cancer made up only a small percentage of all pathogenic ATM mutations, while the majority of positive results were due to a wide range of mutations that may cause varied, more moderate, risks for cancer. 

• We estimate pathogenic mutations in NBN occur in approximately 1/508 individuals in the US population. Although breast cancer screening and prevention guidelines for NBN are based on data pertaining to a specific Slavic founder mutation, the majority of carriers in this cohort were found to have other mutations in NBN; management recommendations may need to be adjusted for such individuals. 

• More research is needed to better understand the wide variety of pathogenic mutation types in ATM and NBN across diverse populations and their contribution to cancer risk.

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