Submissions for variant NM_000038.6(APC):c.7888G>A (p.Val2630Ile) (rs199688874)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254630	SCV000149033	likely benign	not specified	2017-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000115124	SCV000184471	likely benign	Hereditary cancer-predisposing syndrome	2017-03-31	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Counsyl	RCV000409244	SCV000488215	uncertain significance	Familial adenomatous polyposis 1	2016-01-27	criteria provided, single submitter	clinical testing
Invitae	RCV000409244	SCV000552684	uncertain significance	Familial adenomatous polyposis 1	2018-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 2630 of the APC protein (p.Val2630Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199688874, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41517). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics	RCV000409244	SCV000838157	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color	RCV000115124	SCV000910742	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000254630	SCV000918437	likely benign	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: APC c.7888G>A (p.Val2630Ile) 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 was observed with an allele frequency of 0.0001 in 245888 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than 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 Non-Finnish European origin. The variant, c.7888G>A, has been reported in the literature in a validation study (Rey_2017). These report(s) 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance" (2x) or "likely benign" (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034402	SCV000043144	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.