880: Variants of uncertain significance in prenatal microarrays

Abstract

Prenatal chromosomal microarray (CMA) is recommend by SMFM for fetuses with ultrasound anomalies. A limitation of CMA is findings of variants of uncertain significance (VUS). Our objective was to determine how many VUSs were associated with a well-known phenotype, and in each, the level of likelihood of an affected phenotype, with the ultimate goal to establish how many VUSs are truly uncertain. All patients who had prenatal CMA with a VUS reported at our center since 2014 were included. We categorized variants as: variable penetrance; a rare copy number variant (CNV) that includes a gene with a known phenotype; likely autosomal recessive (AR) carrier status; CNV size >1 Mb without disease-causing genes; mosaicism; and region (s) of homozygosity (ROH) >5 Mb or >3% of the genome. For each category, we considered whether the potential phenotype(s) associated with the VUS was known or uncertain. VUSs with variable penetrance, AR carrier status and mosaicism were considered to be associated with a well-described phenotype, while the others were not. We also determined the level of certainty regarding the likelihood of an affected phenotype, which determines our confidence in the information we could provide to the patient regarding the prognosis. VUSs with variable penetrance, AR carrier status, mosaicism and size >1Mb had a known likelihood of having a disease, so were considered to have high certainty in counseling. VUSs due to ROH are known to have a higher risk of disease the larger the size or proportion of the genome, so were also thought to have high certainty in counseling. Rare CNVs were individually examined to determine their likelihood of having an affected phenotype. There were 970 prenatal CMAs performed. Of these, 58 (6.0%) were categorized as a VUS. The number in each category is shown in Table 1. Among the 58 VUSs, 33 (56.9%) were associated with a known phenotype, and 56 (96.6%) were associated with a high level of certainty regarding the likelihood of an affected phenotype. Most VUSs (96.6% of all VUSs, 99.8% of all CMAs) were associated with a high level of certainty regarding the likelihood of an affected phenotype. Variants of truly uncertain significance are relatively uncommon, and most cases can be categorized as to the potential risk of an affected phenotype and what phenotypes are possible.