Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000480278 | SCV000565805 | uncertain significance | not provided | 2022-11-08 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with rectal and/or breast cancer (Pearlman et al., 2017; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 18199528, 27978560, 29684080) |
Color Diagnostics, |
RCV000580908 | SCV000681508 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-07 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with histidine at codon 737 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: 29684080) and rectal cancer (PMID: 27978560). This variant has been identified in 4/250094 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. |
Invitae | RCV002526522 | SCV000768218 | uncertain significance | Familial adenomatous polyposis 1 | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 737 of the APC protein (p.Tyr737His). This variant is present in population databases (rs748868815, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 418611). 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%. 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 | RCV000580908 | SCV001175551 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-09 | criteria provided, single submitter | clinical testing | The p.Y737H variant (also known as c.2209T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 2209. The tyrosine at codon 737 is replaced by histidine, an amino acid with similar properties. This variant was reported in an individual with MMR-proficient rectal cancer diagnosed at age 46 (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471) and was also detected on a 25-gene panel test in a woman of Asian ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was identified by whole-exome sequencing in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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. |