Submissions for variant NM_000038.6(APC):c.6700C>T (p.Pro2234Ser)

gnomAD frequency: 0.00001  dbSNP: rs749507584

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164610	SCV000215273	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-22	criteria provided, single submitter	clinical testing	The p.P2234S variant (also known as c.6700C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 6700. The proline at codon 2234 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002291578	SCV000647662	uncertain significance	Familial adenomatous polyposis 1	2023-11-10	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 2234 of the APC protein (p.Pro2234Ser). This variant is present in population databases (rs749507584, gnomAD 0.002%). 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: 185231). 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.
Color Diagnostics, LLC DBA Color Health	RCV000164610	SCV000681819	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2234 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 2/250468 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	RCV001193537	SCV001362436	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: APC c.6700C>T (p.Pro2234Ser) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245820 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6700C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001566421	SCV001789934	uncertain significance	not provided	2020-05-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25759019)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001566421	SCV002048280	uncertain significance	not provided	2021-06-11	criteria provided, single submitter	clinical testing	The APC c.6700C>T; p.Pro2234Ser variant (rs749507584), to our knowledge, is not reported in the medical literature or gene specific databases. The variant is listed in the ClinVar database (Variation ID: 185231) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 2234 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.594). Due to limited information, the clinical significance of the p.Pro2234Ser variant is uncertain at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291578	SCV002584621	uncertain significance	Familial adenomatous polyposis 1	2022-09-08	criteria provided, single submitter	clinical testing	The APC c.6700C>T (p.Pro2234Ser) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been identified in at least one individual with late-onset colorectal cancer (PMID: 35904628). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV002291578	SCV004203980	uncertain significance	Familial adenomatous polyposis 1	2023-07-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995355	SCV004843445	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2234 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 2/250468 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.