Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000131122 | SCV000186053 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-21 | criteria provided, single submitter | clinical testing | The p.S2000G variant (also known as c.5998A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5998. The serine at codon 2000 is replaced by glycine, an amino acid with similar properties. This alteration was previously reported in an individual with advanced cancer, but specific clinical information was not provided (Mandelker D et al. JAMA, 2017 09;318:825-835). This alteration was detected in a cohort of 76 Malaysian colorectal cancer patients (Abdul Murad NA et al. Dig Dis Sci, 2012 Nov;57:2863-72). This alteration was also seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is not well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003534383 | SCV000814110 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2000 of the APC protein (p.Ser2000Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 142160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780833 | SCV000918431 | uncertain significance | not specified | 2018-03-16 | criteria provided, single submitter | clinical testing | Variant summary: APC c.5998A>G (p.Ser2000Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245622 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5998A>G has been reported in the literature in one individual affected with CRC (Murad 2012). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Color Diagnostics, |
RCV000131122 | SCV004357418 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-30 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with glycine at codon 2000 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 32658311), colorectal cancer (PMID: 22669205), and unspecified advanced cancer (PMID: 28873162). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |