Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000196029 | SCV000254045 | uncertain significance | Familial adenomatous polyposis 1 | 2018-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with threonine at codon 2738 of the APC protein (p.Ile2738Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with an APC-related disease (PMID: 9950360). However, in that individual a pathogenic allele was also identified in APC, which suggests that this c.8213T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216184). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV000564610 | SCV000667502 | likely benign | Hereditary cancer-predisposing syndrome | 2017-06-14 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign) |
| Color | RCV000564610 | SCV000687168 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-10-01 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000196029 | SCV000785389 | uncertain significance | Familial adenomatous polyposis 1 | 2017-08-04 | criteria provided, single submitter | clinical testing | |
| Integrated Genetics/Laboratory Corporation of America | RCV000780867 | SCV000918491 | uncertain significance | not specified | 2018-09-07 | criteria provided, single submitter | clinical testing | Variant summary: APC c.8213T>C (p.Ile2738Thr) results in a non-conservative amino acid change located in the EB-1 binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246018 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8213T>C has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Wallis_1999), however, the patient carried another pathogenic APC variant 1122delTAA, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |