Submissions for variant NM_000038.6(APC):c.4913T>C (p.Met1638Thr)

gnomAD frequency: 0.00002  dbSNP: rs201797422

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213972	SCV000275885	likely benign	Hereditary cancer-predisposing syndrome	2019-01-17	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.
Illumina Laboratory Services, Illumina	RCV000348692	SCV000452018	benign	APC-Associated Polyposis Disorders	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004567582	SCV000647546	uncertain significance	Familial adenomatous polyposis 1	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1638 of the APC protein (p.Met1638Thr). This variant is present in population databases (rs201797422, gnomAD 0.006%). 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: 231898). 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	RCV000213972	SCV000681695	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1638 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). 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 4/251184 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	RCV004525836	SCV000694063	likely benign	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: APC c.4913T>C (p.Met1638Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 1614138 control chromosomes, predominantly at a frequency of 0.0008 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4913T>C has been reported in the literature in individuals affected with Colorectal cancer (CRC) as well as unaffected control study individuals and authors classified this variant as benign (Fujita_2022). The following publication has been ascertained in the context of this evaluation (PMID: 33309985). ClinVar contains an entry for this variant (Variation ID: 231898). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004725081	SCV005338231	uncertain significance	APC-related disorder	2024-04-27	no assertion criteria provided	clinical testing	The APC c.4913T>C variant is predicted to result in the amino acid substitution p.Met1638Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant is interpreted a likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/231898/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.