Submissions for variant NM_000038.6(APC):c.3824G>C (p.Ser1275Thr)

gnomAD frequency: 0.00001  dbSNP: rs587781637

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129750	SCV000184556	likely benign	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000211911	SCV000209519	uncertain significance	not provided	2018-07-26	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3824G>C at the cDNA level, p.Ser1275Thr (S1275T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ser1275Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether APC Ser1275Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000412401	SCV000487768	uncertain significance	Familial adenomatous polyposis 1	2015-11-24	criteria provided, single submitter	clinical testing
Invitae	RCV003315882	SCV000647478	uncertain significance	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1275 of the APC protein (p.Ser1275Thr). This variant is present in population databases (rs587781637, gnomAD 0.004%). 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: 141293). 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	RCV000129750	SCV000905980	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1275 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 5/250608 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.
Genetic Services Laboratory, University of Chicago	RCV001818303	SCV002070194	uncertain significance	not specified	2020-03-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3824G>C, in exon 16 that results in an amino acid change, p.Ser1275Thr. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with an overall low population frequency of 0.0020% (dbSNP rs587781637). The p.Ser1275Thr change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser1275Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1275Thr change remains unknown at this time.
Sema4, Sema4	RCV000129750	SCV002536126	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315882	SCV004018772	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003407543	SCV004109326	uncertain significance	APC-related condition	2023-02-23	criteria provided, single submitter	clinical testing	The APC c.3824G>C variant is predicted to result in the amino acid substitution p.Ser1275Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112175115-G-C) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141293/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000412401	SCV004197778	uncertain significance	Familial adenomatous polyposis 1	2023-10-01	criteria provided, single submitter	clinical testing