Submissions for variant NM_000038.6(APC):c.3245C>G (p.Thr1082Ser)

gnomAD frequency: 0.00004  dbSNP: rs730881244

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211907	SCV000209511	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (PMID: 25142776, 25559809); This variant is associated with the following publications: (PMID: 25142776, 25559809, 28873162, 18199528)
Ambry Genetics	RCV000159547	SCV000215210	likely benign	Hereditary cancer-predisposing syndrome	2021-05-21	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234536	SCV000282734	uncertain significance	Familial adenomatous polyposis 1	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1082 of the APC protein (p.Thr1082Ser). This variant is present in population databases (rs730881244, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25142776, 25559809, 34250417). ClinVar contains an entry for this variant (Variation ID: 181799). 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.
Counsyl	RCV000234536	SCV000489148	uncertain significance	Familial adenomatous polyposis 1	2016-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159547	SCV000910823	likely benign	Hereditary cancer-predisposing syndrome	2016-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211907	SCV001133320	uncertain significance	not provided	2018-12-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159547	SCV002533204	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307414	SCV002600614	uncertain significance	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: APC c.3245C>G (p.Thr1082Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4.4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.3245C>G has been reported in the literature in individuals affected with colorectal cancer (Chubb_2015, Kraus_2015, Pearlman_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002307414	SCV002760352	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000234536	SCV004018733	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	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.
CeGaT Center for Human Genetics Tuebingen	RCV000211907	SCV004159220	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	APC: BP4
Fulgent Genetics, Fulgent Genetics	RCV005031669	SCV005667841	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-01-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724944	SCV005339278	uncertain significance	APC-related disorder	2024-04-02	no assertion criteria provided	clinical testing	The APC c.3245C>G variant is predicted to result in the amino acid substitution p.Thr1082Ser. This variant was observed in patients with colorectal cancer (Table A1, Chubb et al. 2015. PubMed ID: 25559809; Kraus et al. 2015. PubMed ID: 25142776). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/181799/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.