Submissions for variant NM_000038.6(APC):c.5197C>T (p.Pro1733Ser)

dbSNP: rs1441448668

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565711	SCV000667697	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The p.P1733S variant (also known as c.5197C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 5197. The proline at codon 1733 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588797	SCV000694070	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The APC c.5197C>T (p.Pro1733Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense change in one of the SAMP repeat domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/120632 control chromosomes). In the literature, the variant was identified in a colorectal cancer patient as a somatic variant with no loss of heterozygosity detected (Christie_Oncogene_2013). Taken together, this variant is classified as VUS until additional information becomes available.
GeneDx	RCV000588797	SCV002005257	uncertain significance	not provided	2019-06-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23085758, 28767674)
Labcorp Genetics (formerly Invitae), Labcorp	RCV004561718	SCV002126289	uncertain significance	Familial adenomatous polyposis 1	2024-02-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1733 of the APC protein (p.Pro1733Ser). This variant is present in population databases (no rsID available, 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: 482442). 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.
All of Us Research Program, National Institutes of Health	RCV004802220	SCV005424821	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1733 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 been reported in an individual affected with sporadic colorectal cancer (PMID: 23085758). This variant has been identified in 1/250518 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.