Abstract
The utilization of next-generation sequencing technology to interrogate multiple genes simultaneously is being utilized more frequently in hereditary cancer testing. While this has benefits of reducing cost and allowing clinicians to cast a wide net in the elucidation of their patient's cancer, panel testing has the potential to reveal unexpected information. We report on a proband with pathogenic variants resulting in two different hereditary colon cancer syndromes. A 39-year-old male with a history of colon cancer, more than 20 colon polyps and a family history of colon cancer presented for genetic counseling. Testing with a 7-gene high-risk hereditary colon cancer panel identified a homozygous pathogenic variant, c.1187G>A (p.Gly396Asp) in MUTYH, and a likely pathogenic duplication of exon 7 in MSH2. Since this test result, the proband's mother was diagnosed with colon cancer; subsequent genetic testing confirmed she also carries the likely pathogenic duplication in the MSH2 gene. Although the cancer risk in individuals who carry multiple pathogenic variants has not been established for combined biallelic MUTYH-associated polyposis and Lynch syndrome, the identification of multiple pathogenic variants does allow for screening for cancers associated with both syndromes and has implications for cancer risk for family members. In particular, this has significant impact on those who test negative for a known familial pathogenic variant, yet could be still be at risk for cancer due to a second pathogenic variant in a family. More information is needed on the frequency of occurrence of multiple pathogenic variants, as well as the phenotypic spectrum when multiple pathogenic variants are present.
Highlights
A 39-year-old male who works as a general manager presented to the Cancer Genetics Risk Assessment program for genetic counseling due to a personal history of rectal cancer at the age of 38
MUTYH-associated polyposis (MAP), an autosomal recessive condition caused by biallelic pathogenic variants in MUTYH, is characterized by multiple colorectal adenomas arising in adulthood and increased colorectal cancer risk
There is some recent evidence that the incidence of pathogenic variants among individuals diagnosed with colon cancer at a very young age is high, with as many as 14–35% of individuals with colon cancer under age 35 found to carry a pathogenic variant in a variety of different genes (Chubb et al, 2015; Mork et al, 2015)
Summary
A 39-year-old male who works as a general manager presented to the Cancer Genetics Risk Assessment program for genetic counseling due to a personal history of rectal cancer at the age of 38. A similar duplication of exon 7 in the MSH2 gene has been reported previously in a patient affected with colorectal cancer (Casey et al, 2005) Both MUTYH and MSH2 variants were confirmed by using an appropriate orthogonal method. The proband’s mother clarified that she had a diagnosis of vulvar cancer at the age of 34 and five colon polyps at the age of 50 She reported a family history of colorectal cancer in her maternal grandmother at an unknown age, her maternal aunt at the age of 50 and a maternal first cousin at the age of 53; all of this was unknown at the time of the proband’s initial genetic counseling appointment (Figure 2). The proband’s mother was found to carry the likely pathogenic duplication in the MSH2 gene
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