Submissions for variant NM_000038.6(APC):c.3404A>G (p.Tyr1135Cys)

gnomAD frequency: 0.00001  dbSNP: rs754916822

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581738	SCV000686932	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581738	SCV001181670	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	The p.Y1135C variant (also known as c.3404A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3404. The tyrosine at codon 1135 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.
Invitae	RCV003767285	SCV001570299	uncertain significance	Familial adenomatous polyposis 1	2024-01-10	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 1135 of the APC protein (p.Tyr1135Cys). This variant is present in population databases (rs754916822, gnomAD 0.007%). 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: 490262). 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153753	SCV003843567	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001289	SCV004839804	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-03-28	criteria provided, single submitter	clinical testing