This variant, formerly titled COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on a review of the dbSNP and 1000 Genomes Project databases by Hamosh (2018).
Hitchins et al. (2007) described a family in which a 66-year-old woman, the mother of 3 sons by 2 different men, had the clinical picture of hereditary nonpolyposis colorectal cancer (see LYNCH2, 609310). She had metachronous carcinomas that had microsatellite instability and lacked MLH1 expression. The diagnosis of cancer of the endometrium was made at the age of 45; of the colon at age 59; and of the rectum at 60 years. She was heterozygous for a SNP within the MLH1 promoter (rs1800734), with methylation confined to the A allele. In this woman methylation of the A allele on approximately 50% of chromosomes was confirmed by sulfite sequencing. Hitchins et al. (2007) identified an expressible C-T SNP within MLH1 exon 16 in her son, which was used to demonstrate that he was transcribing RNA only from the MLH1 allele inherited from his father. The data were consistent with transmission of the MLH1 epimutation from the proband to her son. In DNA from peripheral blood leukocytes obtained from this son, approximately half of the MLH1 alleles were methylated. In contrast, his sperm had no trace of MLH1 methylation, despite containing equal proportions of alleles derived from his father and mother. Furthermore, analysis of the RNA in his sperm at the MLH1 exon 16 C-T SNP showed reactivation of the maternally derived MLH1 allele. These results indicated reversion of the MLH1 epimutation to normality during spermatogenesis, suggesting a negligible risk of transmission from that family member.
Hamosh (2018) found that the c.-93G-A (NM_000249.3) MLH1 promoter variant was present at a minor allele frequency (MAF) of 0.32 in dbSNP and in 552 of 1,008 East Asian alleles (MAF 55%) in the 1000 Genomes Project database (April 20, 2018), suggesting that the variant is not pathogenic.
