Submissions for variant NM_000038.6(APC):c.5365G>C (p.Val1789Leu)

gnomAD frequency: 0.00001  dbSNP: rs1554086666

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000544335	SCV000647580	uncertain significance	Familial adenomatous polyposis 1	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1789 of the APC protein (p.Val1789Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with attenuated polyposis (PMID: 23561487). ClinVar contains an entry for this variant (Variation ID: 470002). 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. 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.
Ambry Genetics	RCV000563045	SCV000672540	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	clinical testing	The p.V1789L variant (also known as c.5365G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 5365. The valine at codon 1789 is replaced by leucine, an amino acid with highly similar properties. This alteration was seen in an individual diagnosed with attenuated polyposis at age 56, presenting with around 20 polyps at the time of clinical diagnosis (Torrezan GT, Orphanet J Rare Dis 2013 ;8 :54). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000544335	SCV000785266	uncertain significance	Familial adenomatous polyposis 1	2017-06-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000544335	SCV000838132	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563045	SCV000913000	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1789 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 been reported in an individual affected with attenuated form of familial adenomatous polyposis (PMID: 23561487). This variant has not been identified 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.
Myriad Genetics, Inc.	RCV003316714	SCV004019990	uncertain significance	Familial adenomatous polyposis 1	2023-02-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403315	SCV004122222	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: APC c.5365G>C (p.Val1789Leu) 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 250160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5365G>C has been reported in the literature in an individual diagnosed with attenuated polyposis (Torrezan_2013) and others who had multigene panel testing for hereditary cancer (Germani_2020, deOliveira_2021). However, authors of these publications classified the variant as unknown significance. 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. The following publications have been ascertained in the context of this evaluation (PMID: 32957588, 23561487, 35534704). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000544335	SCV004198812	uncertain significance	Familial adenomatous polyposis 1	2023-10-15	criteria provided, single submitter	clinical testing