Submissions for variant NM_000038.6(APC):c.2819C>T (p.Ser940Leu)

dbSNP: rs544709767

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513101	SCV000609168	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV002524126	SCV000647270	uncertain significance	Familial adenomatous polyposis 1	2022-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 940 of the APC protein (p.Ser940Leu). This variant is not present in population databases (gnomAD no frequency). 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: 433634). 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. 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	RCV000580468	SCV000681553	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 940 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV000580468	SCV001177658	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The p.S940L variant (also known as c.2819C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2819. The serine at codon 940 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513101	SCV001470093	uncertain significance	not provided	2020-02-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268134	SCV002550607	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503588	SCV000591121	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ser940Leu variant was not identified in the literature nor was it identified in the 1000 Genomes Project, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (March 14, 2016), Clinvitae, COSMIC, InSiGHT Colon Cancer Gene Variant (LOVD), Zhejiang Colon Cancer (LOVD), ClinVar, GeneInsight – COGR and UMD databases. The variant was identified in dbSNP (ID: rs544709767) as “NA”, but no frequency information was provided; thus the prevalence of this variant in the general population could not be determined. The variant was identified in our lab co-occurring with a pathogenic variant (c.3786_3787delTT) in a case of classical FAP. The p.Ser940 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.