ClinVar Genomic variation as it relates to human health

This missense variant replaces arginine with glutamine at codon 2166 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/281044 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast or ovarian cancer (Tsaousis et al., 2019; Nikitin et al., 2020); This variant is associated with the following publications: (PMID: 31159747, 32547938)

The p.R2166Q variant (also known as c.6497G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 6497. The arginine at codon 2166 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration was also detected in an individual from a cohort of 711 Russian patients with hereditary breast cancer and 60 with sporadic breast cancer. This patient was also found to carry an alteration in the MSH6 gene that was classified as likely pathogenic by the authors (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is 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.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2166 of the APC protein (p.Arg2166Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of APC-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 230267). 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.

This missense variant replaces arginine with glutamine at codon 2166 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 6/281044 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.