<p class="first" id="d1794157e193">Present guidelines for classification of constitutional
variants do not incorporate
inferences from mutations seen in tumors, even when these are associated with a specific
molecular phenotype. When somatic mutations and constitutional mutations lead to the
same molecular phenotype, as for the mismatch repair genes, information from somatic
mutations may enable interpretation of previously unclassified variants. To test this
idea, we first estimated likelihoods that somatic variants in
<i>MLH1</i>,
<i>MSH2</i>,
<i>MSH6</i>, and
<i>PMS2</i> drive microsatellite instability and characteristic IHC staining patterns
by calculating
likelihoods of high versus low normalized variant read fractions of 153 mutations
known to be pathogenic versus those of 760 intronic passenger mutations from 174 paired
tumor-normal samples. Mutations that explained the tumor mismatch repair phenotype
had likelihood ratio for high variant read fraction of 1.56 (95% CI 1.42–1.71) at
sites with no loss of heterozygosity and of 26.5 (95% CI 13.2–53.0) at sites with
loss of heterozygosity. Next, we applied these ratios to 165 missense, synonymous,
and splice variants observed in tumors, combining in a Bayesian analysis the likelihood
ratio corresponding with the adjusted variant read fraction with pretest probabilities
derived from published analyses and public databases. We suggest classifications for
86 of 165 variants: 7 benign, 31 likely benign, 22 likely pathogenic, and 26 pathogenic.
These results illustrate that for mismatch repair genes, characterization of tumor
mutations permits tumor mutation data to inform constitutional variant classification.
We suggest modifications to incorporate molecular phenotype in future variant classification
guidelines.
</p>