Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001026660 | SCV001189089 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-05 | criteria provided, single submitter | clinical testing | The p.R2549H variant (also known as c.7646G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 7646. The arginine at codon 2549 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001043541 | SCV001207292 | uncertain significance | Familial adenomatous polyposis 1 | 2022-09-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2549 of the APC protein (p.Arg2549His). This variant is present in population databases (rs199558585, gnomAD 0.006%). 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: 827170). 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. 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. |
| Color Diagnostics, |
RCV001026660 | SCV001354191 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-31 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 2549 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 an individual affected with colorectal cancer (PMID: 29245953). This variant has been identified in 2/250664 chromosomes 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. |
| St. |
RCV001043541 | SCV001737433 | uncertain significance | Familial adenomatous polyposis 1 | 2021-06-10 | criteria provided, single submitter | clinical testing | The APC c.7646G>A (p.Arg2549His) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/5-112178937-G-A?dataset=gnomad_r2_1). Four of six in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with colorectal cancer (PMID: 29245953). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3. |
| Baylor Genetics | RCV001043541 | SCV004191406 | uncertain significance | Familial adenomatous polyposis 1 | 2023-09-08 | criteria provided, single submitter | clinical testing |