ASPO Abstracts
Analysis of a rare PMS1 variant identified in discordant sibling pairs from hereditary breast cancer families
Category: Molecular Epidemiology & Environment
Conference Year: 2020
Abstract Body:
Background: Additional genes associated with hereditary breast cancer likely exist. We
previously identified a rare and potentially pathogenic PMS1 variant in two affected
sisters from hereditary breast cancer families. This variant was not present in the
unaffected sister-pair. Published in silico analyses previously predicted that this variant
may have functional clinical significance.
Objectives: 1.) To determine the genotype-phenotype correlation within the two families wi
with the rare PMS1 variant. 2.) To sequence PMS1 mRNA from cell lines with and wi
without the c.605G>A variant to test the hypothesis that the PMS1 c.605G>A germline va
variant disrupts PMS1 mRNA splicing.
Methods: 1.) Germline DNA from extended family members were collected and analyzed
to determine if the PMS1 c.605G>A variant tracks with affected family members. 2.)
Using NCI-H441 lung cancer cells heterozygous for the PMS1 c.605G>A variant we s
sequenced PMS1 mRNA and compared the results with cell lines harboring WT PMS1 to d
determine whether PMS1 c.605G>A impacts exon 6 utilization.
Results: The PMS1 c.605G>A variant did not track with cancer in either family. No
PMS1 c.605G>A variant-dependent differences in exon 6 utilization were detected
between PMS1 WT cell lines and the NCI-H441 cells.
Conclusions: Given the PMS1 c.605G>A variant did not segregate with disease and
there was no variant-dependent impact on splicing; the PMS1 c.605G>A variant is likely b
benign. This information can help others investigating functional significance of either s
somatic or germline mutations.
Keywords: hereditary breast cancer, family based design, genotype-phenotype correlation phenotype correlation