Submissions for variant NM_000038.6(APC):c.5194A>G (p.Met1732Val)

gnomAD frequency: 0.00001  dbSNP: rs752065261

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000338065	SCV000452021	uncertain significance	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV003475934	SCV000552648	uncertain significance	Familial adenomatous polyposis 1	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1732 of the APC protein (p.Met1732Val). This variant is present in population databases (rs752065261, 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: 350414). 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.
GeneDx	RCV000482902	SCV000564575	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing	This variant is denoted APC c.5194A>G at the cDNA level, p.Met1732Val (M1732V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met1732Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met1732Val is located in a beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Met1732Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573682	SCV000667401	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The p.M1732V variant (also known as c.5194A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5194. The methionine at codon 1732 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV000779704	SCV000916457	uncertain significance	not specified	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The APC c.5194A>G (p.Met1732Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/245306 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000573682	SCV001353229	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1732 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 3/250548 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482902	SCV002047215	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000012 (3/250548 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV000779704	SCV002071924	uncertain significance	not specified	2021-10-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.5194A>G, in exon 16 that results in an amino acid change, p.Met1732Val. This sequence change does not appear to have been previously described in individuals with APC-related disorders. This sequence change has been described in one south Asian individual and two non-Finnish European individuals in the gnomAD population database (dbSNP rs752065261). The p.Met1732Val 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.Met1732Val substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Met1732Val change remains unknown at this time.
Baylor Genetics	RCV003475934	SCV004201322	uncertain significance	Familial adenomatous polyposis 1	2023-08-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356468	SCV001551645	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Met1732Val variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs752065261) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, and three other submitters). The variant was identified in control databases in 3 of 245306 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 110926 chromosomes (freq: 0.00002) and South Asian in 1 of 30766 chromosomes (freq: 0.00003), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Met1732 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.