Submissions for variant NM_000038.6(APC):c.7550A>G (p.Tyr2517Cys)

gnomAD frequency: 0.00002  dbSNP: rs587783036

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144574	SCV000282825	uncertain significance	Familial adenomatous polyposis 1	2024-01-11	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 2517 of the APC protein (p.Tyr2517Cys). This variant is present in population databases (rs587783036, gnomAD 0.01%). 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: 156483). 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.
GeneDx	RCV000759443	SCV000566783	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or leukemia (PMID: 33606809, 30102335, 26580448); This variant is associated with the following publications: (PMID: 30102335, 33606809, 26580448)
Ambry Genetics	RCV000572226	SCV000667306	likely benign	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000572226	SCV000681875	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2517 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 familial polyposis syndrome in the literature. This variant has been identified in 4/251038 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.
Mendelics	RCV003492634	SCV000838153	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759443	SCV000888765	uncertain significance	not provided	2018-03-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572226	SCV002528171	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
Baylor Genetics	RCV000144574	SCV004198901	uncertain significance	Familial adenomatous polyposis 1	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998160	SCV004835689	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2517 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 familial polyposis syndrome in the literature. This variant has been identified in 4/251038 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.
Pathway Genomics	RCV000144574	SCV000189873	uncertain significance	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739467	SCV005364778	uncertain significance	APC-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The APC c.7550A>G variant is predicted to result in the amino acid substitution p.Tyr2517Cys. This variant was reported as a variant of uncertain significance in an individual with pediatric cancer (Table S4a. Zhang et al. 2015. PubMed ID: 26580448) and in an individual with breast cancer (Table S4. Sandoval et al. 2021. PubMed ID: 33606809). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretation of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/156483/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.