ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2957A>G (p.Tyr986Cys)

dbSNP: rs730881243
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159545 SCV000209509 uncertain significance not provided 2014-09-17 criteria provided, single submitter clinical testing This variant is denoted APC c.2957A>G at the cDNA level, p.Tyr986Cys (Y986C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Tyr986Cys 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 Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr986Cys occurs at a position that is highly conserved across species and is located in a region responsible for down-regulation through a process mediated by direct ubiquitination (UniProt). 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 Tyr986Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563690 SCV000667233 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-01 criteria provided, single submitter clinical testing The p.Y986C variant (also known as c.2957A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 2957. The tyrosine at codon 986 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
Color Diagnostics, LLC DBA Color Health RCV000563690 SCV000686919 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-11 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 986 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 1/251300 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 RCV002229758 SCV000827283 uncertain significance Familial adenomatous polyposis 1 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 986 of the APC protein (p.Tyr986Cys). This variant is present in population databases (rs730881243, gnomAD 0.003%). 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: 181797). 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.
Baylor Genetics RCV003462064 SCV004207868 uncertain significance Familial adenomatous polyposis 1 2023-05-30 criteria provided, single submitter clinical testing

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