Submissions for variant NM_000038.6(APC):c.7391C>A (p.Ser2464Tyr)

gnomAD frequency: 0.00002  dbSNP: rs766473931

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516295	SCV000282818	uncertain significance	Familial adenomatous polyposis 1	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 2464 of the APC protein (p.Ser2464Tyr). This variant is present in population databases (rs766473931, gnomAD 0.006%). 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: 236643). 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 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	RCV000484267	SCV000570472	uncertain significance	not provided	2016-05-24	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7391C>A at the cDNA level, p.Ser2464Tyr (S2464Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in The Cancer Genome Atlas of tumors (Gnad 2015). APC Ser2464Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Ser2464Tyr occurs at a position that is conserved across species and is not located in a known functional domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Ser2464Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000776318	SCV000911647	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 2464 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 4/251042 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.
Ambry Genetics	RCV000776318	SCV001188735	likely benign	Hereditary cancer-predisposing syndrome	2021-05-25	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.
Baylor Genetics	RCV002516295	SCV004203268	uncertain significance	Familial adenomatous polyposis 1	2023-07-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998688	SCV004835672	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 2464 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 4/251042 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.