Submissions for variant NM_000038.6(APC):c.8146G>T (p.Val2716Leu)

dbSNP: rs587778044

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478199	SCV000564588	uncertain significance	not provided	2014-10-15	criteria provided, single submitter	clinical testing	This variant is denoted APC c.8146G>T at the cDNA level, p.Val2716Leu (V2716L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Val2716Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. APC Val2716Leu occurs at a position that is poorly conserved across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Val2716Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV003766654	SCV001564791	uncertain significance	Familial adenomatous polyposis 1	2021-09-15	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 418015). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 2716 of the APC protein (p.Val2716Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155200	SCV003844781	uncertain significance	not specified	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: APC c.8146G>T (p.Val2716Leu) 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 absent in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8146G>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (MSH2 c.842C>G, p.S281X), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.