TY - JOUR
T1 - The germline MLH1 K618A variant and susceptibility to lynch syndrome-associated tumors
AU - Medeiros, Fabiola
AU - Lindor, Noralane M.
AU - Couch, Fergus J.
AU - Highsmith, W. Edward
N1 - Funding Information:
This work was supported in part by the National Cancer Institute, NIH, under RFA #CA-95-011 via the Mayo Clinic Colon Cancer Family Registry ( UO1 CA074800 ). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute nor any of the collaborating centers in the Cancer Family Registries, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
PY - 2012
Y1 - 2012
N2 - Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.
AB - Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.
UR - http://www.scopus.com/inward/record.url?scp=84859582906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859582906&partnerID=8YFLogxK
U2 - 10.1016/j.jmoldx.2012.01.006
DO - 10.1016/j.jmoldx.2012.01.006
M3 - Article
C2 - 22426235
AN - SCOPUS:84859582906
SN - 1525-1578
VL - 14
SP - 264
EP - 273
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 3
ER -