Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas

Abstract

Biallelic germline mutations in the base excision repair gene MYH have been reported in patients with multiple colorectal adenomas and cancer and in sporadic FAP patients not showing a detectable APC germline mutation. In this study, the prevalence of the common Y165C and G382D germline variants of the MYH gene was examined in 70 FAP/AAPC patients with no detectable APC mutation and a family history compatible with recessive inheritance. In addition, 141 normal-population adenoma patients (mean number of adenomas, 2.8; range, 1-9) and 52 clean colon controls were studied. The entire coding region of the MYH gene was analyzed in Y165C or G382D heterozygous patients. Since the same second mutational event (a 3 bp deletion in exon 14, 1395delGGA) was detected in 3 patients, the prevalence of this variant was also examined in all groups. In all, 14 of 70 patients in the FAP/AAPC group (20%; 95% CI ‫؍‬ 11.7-31.6%) had biallelic germline MYH variants and 3 were heterozygotes (4.3%). None of the 141 normal-population adenoma patients carried biallelic germline MYH variants (95% CI ‫؍‬ 0.06 -4.1%) and 3 were heterozygotes (2.1%). In the control group, no MYH variants were detected. These results indicated that MYH-associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population. In addition, our data suggest that mutation 1395delGGA is a subpolymorphic MYH mutational event in some Caucasian populations.

A novel functionally deficientMYH variant in individuals with colorectal adenomatous polyposis

“…Also, another variant in the MYH exon 14, c.1395-7delGGA, has been identified in Caucasians, but no functional testing has been performed. The c.1395-7delGGA change has been described in compound heterozygosity in one British and five Italian patients, and in homozygosity in one Italian patient, all compatible with FAP phenotype (Fleischmann, et al, 2004;Gismondi, et al, 2004).…”

“…In previous studies, MYH-associated tumors have shown a high frequency of G>T mutations in APC and KRAS, in accordance with defective BER (Al-Tassan, et al, 2002;Jones, et al, 2004;. Approximately 85% of Caucasian patients with MYH mutations carry the (c.494A>G) p.Y165C or (c.1145G>A) p.G382D variants, and only about twelve other likely pathogenic variants [(c.970C>T) Fleischmann, et al, 2004;Gismondi, et al, 2004;Isidro, et al, 2004;. However, specific variants have been identified in different ethnic populations, including (c.1396G>T) p.E466X in the Indian and (c.270C>A) p.Y90X in the Pakistani population .…”

Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations

“…From the total number of patients within this group of families no genotype/phenotype correlations could be identified. In comparison, the disease characteristics of the respective family members of the patients who were shown to harbour other MYH mutations are also shown in Table II (patients [11][12][13][14][15][16][17][18][19]. The average age of diagnosis was 53.9 years of age.…”

“…Both common mutations have been shown to affect a functional change in the MYH gene, which are believed to be pathogenic. 18 A report on an Italian population identified a 3 base pair deletion (1395delGGA), which was considered common in that population. 18 Since there are a considerable proportion of Italian descendants living in Australia the 1395delGGA was also assessed for its frequency.…”

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

“…1,[98][99][100] Although a number of mutations in the MUTYH gene have been documented, two missense mutations, p.Y165C and p.G382D, account for 70-80% of mutant alleles in the Northern European population, with a third mutation, 1395delGGA, accounting for ~25% of mutant alleles in persons of a Southern European (Mediterranean) background. 101 The common missense mutations in MUTYH, p.Y165C and p.G382D, have a well-established effect on glycosylase function in experimental systems. More recently, additional missense changes have been reported.…”