ClinVar Genomic variation as it relates to human health

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)

In a 39-year-old Ashkenazi Jewish man with colorectal adenomas and a family history of colon cancer (175100), Laken et al. (1997) identified a 3920T-A transversion in the APC gene, resulting in an ile1307-to-lys (I1307K) substitution. An in vitro synthesized protein assay from this allele showed a truncated APC protein. The T-to-A change converted an AAATAAAA sequence to (A)8 and was postulated to result in failure of the cellular transcriptional or translational machinery, resulting in a truncated protein. The (A)8 tract not only was unstable in vivo, leading to somatic mutation, but also appeared to be unstable in vitro during the enzymatic manipulations employed in the IVSP assay. The same mutation was identified in 28% of Ashkenazi Jews with a family history of CRC and in the carrier state of 6% unaffected Ashkenazim from the general population. Analysis of tumor tissue occurring in CRC patients with the I1307K mutation revealed that nearly half contained somatic truncating mutations closely surrounding the germline mutation; all the somatic mutations occurred exclusively in the I1307K allele. Laken et al. (1997) concluded that presence of the I1307K mutation results in a 2-fold increased risk for colorectal cancer, although the change in itself does not likely contribute to the disease. Petersen et al. (1998) addressed the increasingly important problem of interpreting the significance of missense mutations found in disease-causing genes, citing the APC I1307K mutation as a case in point. Using a Bayesian approach that incorporated genetic information on affected relatives, relationship of the relatives to the proband, the population frequency of the mutation, and the phenocopy rate of the disease, the authors concluded that the I1307K mutation was likely to be disease causing. Petersen et al. (1998) also developed a simple approximation for rare alleles and considered the case of unknown penetrance and allele frequency. By genotyping 5,081 Ashkenazi volunteers in a community survey, Woodage et al. (1998) concluded that APC I1307K carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage et al. (1998) emphasized that the large majority of I1307K carriers would not develop cancer of the colon or breast, and that only a small proportion of Jewish individuals who develop these cancers will be carriers. Redston et al. (1998) identified a heterozygous I1307K polymorphism in 66 (10.4%) of 632 unrelated Ashkenazi Jewish women with primary invasive breast cancer (113705). This proportion was significantly greater than the 7.03% carrier frequency observed in the study by Woodage et al. (1998). However, prevalence data suggested that the effect of the I1307K allele on breast cancer risk was largely or entirely limited to those with BRCA (see, e.g., BRCA1, 113705) founder mutations. Redston et al. (1998) concluded that the I1307K polymorphism emerges as a candidate low-penetrance breast cancer susceptibility allele or a genetic modifier of risk in BRCA heterozygotes. Frayling et al. (1998) identified the I1307K allele in 3 patients of Ashkenazi Jewish descent with multiple colorectal adenomas and/or carcinoma. Yuan et al. (1998) described a French Canadian kindred in which HNPCC was related to a novel truncating mutation in the MLH1 gene (120436.0009). In the same family, they found the I1307K APC polymorphism, which had previously been identified only in individuals of self-reported Ashkenazi Jewish origin. However, there appeared to be no relationship between the I1307K polymorphism and the presence or absence of cancer in the French Canadian family. Gryfe et al. (1999) identified the APC I1307K allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC I1307K allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P equal to 0.01). Compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Gryfe et al. (1999) estimated that the APC I1307K polymorphism directly contributes to 3 to 4% of all Ashkenazi Jewish colorectal cancer. In persons at average risk for colorectal cancer, Rozen et al. (1999) identified the APC I1307K variant in 5.0% of 120 European and 1.6% of 188 non-European Jews (P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer (P = 0.02), and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred individually or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia. Prior et al. (1999) did not identify the I1307K mutation among 345 non-Ashkenazim individuals with colorectal cancer, suggesting that it is restricted to that population. Somatic mutations occurred at a lower frequency and were more randomly distributed when the I1307K allele was not present. In an editorial, Gruber et al. (1999) compared the group of Prior et al. (1999) to investigators at the scene of an accident. Prior et al. (1999) carefully characterized the somatic mutations associated with the I1307K polymorphism as if they were crash sites near this hypermutability oil slick. Tumors with the wildtype allele at codon 1307 had a variety of somatic mutations that were distributed randomly in the APC gene and were not tightly clustered around the 1307 codon. These results contrasted sharply with previous crash site investigations of the mutant allele which showed characteristic mutations piling up like cars around the oil slick. This earlier work by the Vogelstein group (Laken et al., 1997), confirmed by Gryfe et al. (1998), showed that mutations arising in association with the mutant allele appeared to be localized to a 29-bp region around the gene and were almost always insertions. Furthermore, these unusual somatic mutations were restricted to the mutant allele, never occurring in the wildtype allele in the same patients. The reference to 'crash sites' and 'oil slick' provided useful imagery comparable to the 'gatekeeper' and 'caretaker' roles of other cancer-related genes--again products of the Vogelstein laboratory, as is the designation 'landscaper,' envisioned as the basis of colorectal cancer in juvenile polyposis. Patael et al. (1999) found the I1307K polymorphism in 2 non-Ashkenazi Jewish women in Israel and hypothesized that among Jewish persons it may not be restricted to Ashkenazim, but may actually reflect a common ancestral polymorphism. The haplotype pattern in these 2 women and in 9 Ashkenazi carrier controls was identical in all individuals regardless of ethnic origin. Lamlum et al. (2000) screened 164 unrelated patients with multiple (3-100) colorectal adenomas for germline variants throughout the APC gene, and found 3 Ashkenazi patients harboring the I1307K mutation. Germline APC variants accounted for approximately 10% of all patients with multiple adenomas. The authors recommended screening multiple adenoma patients of Ashkenazi descent for the I1307K variant. Silverberg et al. (2001) found no increased frequency of I1307K in Ashkenazi Jewish patients with inflammatory bowel disease and concluded that this mutation cannot account for the increased susceptibility to colorectal cancer associated with inflammatory bowel disease. Rozen et al. (2002) reported studies in Israel indicating that I1307K is a low-penetrance variant with a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. They concluded that I1307K is a founder variant in Jews of different ethnic origin, mainly Ashkenazim, and it explains only partially their higher incidence of colorectal carcinoma. Lynch and de la Chapelle (2003) schematized the somatic mutations that occur in carriers of the I1307K polymorphism, which results in a stretch of 8 adenosines that is believed to increase the risk of somatic mutations as a result of slippage during replication. Lynch and de la Chapelle (2003) illustrated the types of somatic changes in colonic tumors, e.g., an addition of 1 adenosine seen in the affected allele of many carriers. The addition or loss of a nucleotide causes a frameshift and loss of function of APC, constituting an important somatic event in tumor initiation. In individuals of Ashkenazi, Sephardi, and Arab descent, Niell et al. (2003) found a common progenitor haplotype spanning across APC I1037K from the centromeric marker D5S135 to the telomeric marker D5S346. The ancestor of modern I1307K alleles existed 87.9 to 118 generations ago (approximately 2,200 to 2,950 years ago). This estimate indicated that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. The data did not indicate that selection operated at I1307K, providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection. (less)

In a 39-year-old Ashkenazi Jewish man with colorectal adenomas and a family history of colon cancer (175100), Laken et al. (1997) identified a 3920T-A transversion in the APC gene, resulting in an ile1307-to-lys (I1307K) substitution. An in vitro synthesized protein assay from this allele showed a truncated APC protein. The T-to-A change converted an AAATAAAA sequence to (A)8 and was postulated to result in failure of the cellular transcriptional or translational machinery, resulting in a truncated protein. The (A)8 tract not only was unstable in vivo, leading to somatic mutation, but also appeared to be unstable in vitro during the enzymatic manipulations employed in the IVSP assay. The same mutation was identified in 28% of Ashkenazi Jews with a family history of CRC and in the carrier state of 6% unaffected Ashkenazim from the general population. Analysis of tumor tissue occurring in CRC patients with the I1307K mutation revealed that nearly half contained somatic truncating mutations closely surrounding the germline mutation; all the somatic mutations occurred exclusively in the I1307K allele. Laken et al. (1997) concluded that presence of the I1307K mutation results in a 2-fold increased risk for colorectal cancer, although the change in itself does not likely contribute to the disease. Petersen et al. (1998) addressed the increasingly important problem of interpreting the significance of missense mutations found in disease-causing genes, citing the APC I1307K mutation as a case in point. Using a Bayesian approach that incorporated genetic information on affected relatives, relationship of the relatives to the proband, the population frequency of the mutation, and the phenocopy rate of the disease, the authors concluded that the I1307K mutation was likely to be disease causing. Petersen et al. (1998) also developed a simple approximation for rare alleles and considered the case of unknown penetrance and allele frequency. By genotyping 5,081 Ashkenazi volunteers in a community survey, Woodage et al. (1998) concluded that APC I1307K carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage et al. (1998) emphasized that the large majority of I1307K carriers would not develop cancer of the colon or breast, and that only a small proportion of Jewish individuals who develop these cancers will be carriers. Redston et al. (1998) identified a heterozygous I1307K polymorphism in 66 (10.4%) of 632 unrelated Ashkenazi Jewish women with primary invasive breast cancer (113705). This proportion was significantly greater than the 7.03% carrier frequency observed in the study by Woodage et al. (1998). However, prevalence data suggested that the effect of the I1307K allele on breast cancer risk was largely or entirely limited to those with BRCA (see, e.g., BRCA1, 113705) founder mutations. Redston et al. (1998) concluded that the I1307K polymorphism emerges as a candidate low-penetrance breast cancer susceptibility allele or a genetic modifier of risk in BRCA heterozygotes. Frayling et al. (1998) identified the I1307K allele in 3 patients of Ashkenazi Jewish descent with multiple colorectal adenomas and/or carcinoma. Yuan et al. (1998) described a French Canadian kindred in which HNPCC was related to a novel truncating mutation in the MLH1 gene (120436.0009). In the same family, they found the I1307K APC polymorphism, which had previously been identified only in individuals of self-reported Ashkenazi Jewish origin. However, there appeared to be no relationship between the I1307K polymorphism and the presence or absence of cancer in the French Canadian family. Gryfe et al. (1999) identified the APC I1307K allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC I1307K allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P equal to 0.01). Compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Gryfe et al. (1999) estimated that the APC I1307K polymorphism directly contributes to 3 to 4% of all Ashkenazi Jewish colorectal cancer. In persons at average risk for colorectal cancer, Rozen et al. (1999) identified the APC I1307K variant in 5.0% of 120 European and 1.6% of 188 non-European Jews (P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer (P = 0.02), and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred individually or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia. Prior et al. (1999) did not identify the I1307K mutation among 345 non-Ashkenazim individuals with colorectal cancer, suggesting that it is restricted to that population. Somatic mutations occurred at a lower frequency and were more randomly distributed when the I1307K allele was not present. In an editorial, Gruber et al. (1999) compared the group of Prior et al. (1999) to investigators at the scene of an accident. Prior et al. (1999) carefully characterized the somatic mutations associated with the I1307K polymorphism as if they were crash sites near this hypermutability oil slick. Tumors with the wildtype allele at codon 1307 had a variety of somatic mutations that were distributed randomly in the APC gene and were not tightly clustered around the 1307 codon. These results contrasted sharply with previous crash site investigations of the mutant allele which showed characteristic mutations piling up like cars around the oil slick. This earlier work by the Vogelstein group (Laken et al., 1997), confirmed by Gryfe et al. (1998), showed that mutations arising in association with the mutant allele appeared to be localized to a 29-bp region around the gene and were almost always insertions. Furthermore, these unusual somatic mutations were restricted to the mutant allele, never occurring in the wildtype allele in the same patients. The reference to 'crash sites' and 'oil slick' provided useful imagery comparable to the 'gatekeeper' and 'caretaker' roles of other cancer-related genes--again products of the Vogelstein laboratory, as is the designation 'landscaper,' envisioned as the basis of colorectal cancer in juvenile polyposis. Patael et al. (1999) found the I1307K polymorphism in 2 non-Ashkenazi Jewish women in Israel and hypothesized that among Jewish persons it may not be restricted to Ashkenazim, but may actually reflect a common ancestral polymorphism. The haplotype pattern in these 2 women and in 9 Ashkenazi carrier controls was identical in all individuals regardless of ethnic origin. Lamlum et al. (2000) screened 164 unrelated patients with multiple (3-100) colorectal adenomas for germline variants throughout the APC gene, and found 3 Ashkenazi patients harboring the I1307K mutation. Germline APC variants accounted for approximately 10% of all patients with multiple adenomas. The authors recommended screening multiple adenoma patients of Ashkenazi descent for the I1307K variant. Silverberg et al. (2001) found no increased frequency of I1307K in Ashkenazi Jewish patients with inflammatory bowel disease and concluded that this mutation cannot account for the increased susceptibility to colorectal cancer associated with inflammatory bowel disease. Rozen et al. (2002) reported studies in Israel indicating that I1307K is a low-penetrance variant with a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. They concluded that I1307K is a founder variant in Jews of different ethnic origin, mainly Ashkenazim, and it explains only partially their higher incidence of colorectal carcinoma. Lynch and de la Chapelle (2003) schematized the somatic mutations that occur in carriers of the I1307K polymorphism, which results in a stretch of 8 adenosines that is believed to increase the risk of somatic mutations as a result of slippage during replication. Lynch and de la Chapelle (2003) illustrated the types of somatic changes in colonic tumors, e.g., an addition of 1 adenosine seen in the affected allele of many carriers. The addition or loss of a nucleotide causes a frameshift and loss of function of APC, constituting an important somatic event in tumor initiation. In individuals of Ashkenazi, Sephardi, and Arab descent, Niell et al. (2003) found a common progenitor haplotype spanning across APC I1037K from the centromeric marker D5S135 to the telomeric marker D5S346. The ancestor of modern I1307K alleles existed 87.9 to 118 generations ago (approximately 2,200 to 2,950 years ago). This estimate indicated that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. The data did not indicate that selection operated at I1307K, providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection. (less)