Submissions for variant NM_000038.6(APC):c.4913T>C (p.Met1638Thr) (rs201797422)

Total submissions: 5

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	In silico models in agreement (benign);Other strong data supporting benign classification
Illumina Clinical Services Laboratory,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.
Invitae	RCV000549046	SCV000647546	uncertain significance	Familial adenomatous polyposis 1	2019-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with threonine at codon 1638 of the APC protein (p.Met1638Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs201797422, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 231898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	RCV000213972	SCV000681695	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-15	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000586239	SCV000694063	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The APC c.4913T>C (p.Met1638Thr) variant involves the alteration of a conserved nucleotide located in the Adenomatous polyposis coli protein repeat region (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121374 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000116 (1/8654). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this might be a benign polymorphism found primarily in the populations of East Asian origin. However, the allele number is very small. In addition, one other clinical diagnostic laboratory classified this variant as uncertain significance and another one classified it as Likely benign, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; 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.