Preconception carrier screening yield: effect of variants of unknown significance in partners of carriers with clinically significant variants

Hila Fridman, Doron M. Behar, Shai Carmi, Ephrat Levy-Lahad*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Purpose: Expanded preconception carrier screening (ECS) identifies at-risk couples (ARCs) for multiple diseases. ECS reports currently include only pathogenic/likely pathogenic variants (P/LPVs). Variants of unknown significance (VUS) are not reported, unlike genomic or chromosomal array test results in other post/prenatal settings. Couples who are P/LP and VUS carriers (P/LP*VUS) may be at risk, particularly in genes with high P/LP carrier rates. We examined the possible contribution of P/LP*cVUS (coding, nonsynonymous VUS) matings to ECS yield in an Ashkenazi Jewish cohort, a population with well-established preconception screening. Methods: We analyzed 672 Ashkenazi Jewish genome sequences (225,456 virtual matings) for variants in three different gene sets and calculated the rates of P/LP*P/LP and P/LP*cVUS matings. Results: Across 180 genes, we identified 4671 variants: 144 (3.1%) P/LP and 1963 (42%) VUS. Across gene sets, the proportion of P/LP*P/LP and P/LP*cVUS ARCs was 2.7–3.8% and 6.8–7.5%, respectively. Conclusion: Disregarding VUS in ECS may miss ARCs. Even if only 10% of couples currently classified as P/LP*cVUS are ultimately reclassified as P/LP*P/LP, ECS yield would increase by ≈20%. While current understanding of VUS precludes VUS reporting in ECS, these findings underscore the importance of VUS reclassification. This will crucially depend on enlarging population frequency databases, especially of affected individuals.

Original languageAmerican English
Pages (from-to)646-653
Number of pages8
JournalGenetics in Medicine
Issue number3
StatePublished - 1 Mar 2020

Bibliographical note

Funding Information:
S.C. thanks the Israel Science Foundation Grant 407/17 and the Abisch Frenkel Foundation. We thank the Ashkenazi Genome Consortium for the AJ genomic data.

Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.


  • Ashkenazi Jewish genetics
  • VUS
  • preconception expanded carrier screening
  • variant classification


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