ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6124T>C (p.Cys2042Arg)

dbSNP: rs730881254
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211924 SCV000209536 uncertain significance not provided 2014-09-17 criteria provided, single submitter clinical testing This variant is denoted APC c.6124T>C at the cDNA level, p.Cys2042Arg (C2042R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Cys2042Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Cys2042Arg occurs at a position that is highly conserved across species and is located in SAMP repeat/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Cys2042Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159564 SCV000217127 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-08 criteria provided, single submitter clinical testing The p.C2042R variant (also known as c.6124T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 6124. The cysteine at codon 2042 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in an individual with familial colorectal cancer but not polyposis (Rohlin A et al. Fam Cancer, 2017 04;16:195-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003743597 SCV000647628 uncertain significance Familial adenomatous polyposis 1 2023-02-22 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 181812). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2042 of the APC protein (p.Cys2042Arg). This variant is present in population databases (rs730881254, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with APC-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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, LLC DBA Color Health RCV000159564 SCV000905992 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-05 criteria provided, single submitter clinical testing This missense variant replaces cysteine with arginine at codon 2042 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with mismatch repair stable colorectal cancer (PMID: 27696107). This variant has been identified in 1/250848 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.

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