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

gnomAD frequency: 0.00001  dbSNP: rs754916822

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767285	SCV001570299	likely pathogenic	Familial adenomatous polyposis 1	2025-01-28	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 missense change has been observed in individual(s) with clinical features of familial adenomatous polyposis (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 490262). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1135 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 2/250872 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240229	SCV005885974	likely pathogenic	Familial multiple polyposis syndrome	2025-02-18	criteria provided, single submitter	clinical testing	Variant summary: APC c.3404A>G (p.Tyr1135Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250872 control chromosomes. c.3404A>G has been reported in the heterozygous state as a de novo variant (maternity and paternity confirmed) internally in at least 1 individual affected with clinical features of APC-related hereditary cancer (example, Labcorp Genetics (formerly Invitae)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 490262). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357730	SCV005913519	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1	2021-03-12	criteria provided, single submitter	clinical testing