Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes

Abstract

Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS. Power to classify VUS was higher for Chinese than United States pedigrees. The number of affected individuals explained the most variation in LODadj (21–38%). The distance to the furthest affected relative from the proband explained 1–7% of the variation for the benign VUS and Lynch associated cancers. Minimum age of onset explained 5–13% of the variation in families with pathogenic breast/ovarian cancer variants. Random removal of 50% of the phenotype/genotype data reduced power and the variation in LODadj was best explained by the distance to the furthest affected relative followed by the number of affected individuals and minimum age of onset when the founder was only 2 generations from the proband. Power to classify benign variants was ~2× power to classify pathogenic variants. Affecteds-only analysis resulted in virtually no power to correctly classify benign variants and reduced power to classify pathogenic variants. These results can be used to guide recruitment efforts to classify rare and private VUS.

A comparison of cosegregation analysis methods for the clinical setting

“…There is simply not enough information in the average U.S. family to classify variants in BRCA1 or MLH1 , using cosegregation analysis alone. Although bigger families would provide more evidence[1], these are not commonly seen in the clinical setting.…”

“…Cosegregation analysis can be an important component of evaluating the pathogenicity of newly identified genetic variants in cancer risk genes. For cancer traits, the power of cosegregation analysis depends largely on the number of genotyped individuals in the pedigree, the distance of relationship between affected individuals, and the minimum age of disease onset in affected individuals[1]. Regardless of the strength of evidence from any specific pedigree, the results of quantitative cosegregation results can be used to support either benign or pathogenic classification in multifactorial analysis[2].…”

The use of segregation analysis in interpretation of sequence variants in SMAD3: A case report

“…The suggestion that specific disease group experts should continue to develop adapted evidence regarding the classification of variants in specific genes because the applicability and weight assigned to certain criteria may vary by gene and disease (Richards et al, 2015 ) has already been addressed for certain groups (Moghadasi et al, 2016 ; Rosenthal et al, 2017 ). The cases in the present report illustrate the relevance of such an action in the group HTAAD that frequently presents with sequence variants of uncertain significance (Pope et al, 2019 ).…”

Patient goals, motivations, and attitudes in a patient‐driven variant reclassification study

“…The FindMyVariant study used various methods to reclassify variants, including the 2015 ACMG/AMP guidelines (Richards et al, 2015), in-house functional data, laboratory data, and tumor studies, publicly available data in population databases such as gno-mAD and ExAC (Lek et al, 2016) and laboratory databases such as ClinVar (Landrum et al, 2013), and cosegregation analysis (Rañola et al, 2017;Rosenthal et al, 2017;Thompson, Easton, & Goldgar, 2003). Cosegregation data was obtained by testing family members for the familial variant free of charge with saliva kits.…”

“…Cosegregation analysis can be used to determine if a variant segregates with a trait more often than expected by chance. Its effectiveness depends on gene penetrance, the number of relatives tested in a family, and the relationship between affected individuals (Rañola, Liu, Rosenthal, & Shirts, ; Rosenthal, Ranola, & Shirts, ). Access to family studies at most commercial laboratories is controlled and limited by the laboratory, and there can be multiple barriers to entry, including formal application processes, potential fees for participants, and eligibility limited by individual laboratory interest about specific genes or the presence of available affected relatives (Garrett et al, ).…”