Submissions for variant NM_000038.6(APC):c.8017A>G (p.Arg2673Gly)

gnomAD frequency: 0.00002  dbSNP: rs767286063

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534471	SCV000254044	uncertain significance	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2673 of the APC protein (p.Arg2673Gly). This variant is present in population databases (rs767286063, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of APC-related conditions (PMID: 29684080, 35189564). ClinVar contains an entry for this variant (Variation ID: 216183). 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.
GeneDx	RCV000766698	SCV000570747	uncertain significance	not provided	2019-08-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29684080, 28706299)
Ambry Genetics	RCV000572076	SCV000667366	likely benign	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000572076	SCV000681903	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2673 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. Large case studies detected no significant association with pancreatic cancer (PMID: 32980694), or colorectal cancer (PMID: 33309985). This variant has been identified in 4/251230 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	RCV000202229	SCV001362378	uncertain significance	not specified	2019-08-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.8017A>G (p.Arg2673Gly) results in a non-conservative amino acid change located in the EB-1 binding domain of 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 1.6e-05 in 251230 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8017A>G has been reported in the literature in a cohort of patients with features of Cowden/Cowden-like and Bannayan-Riley-Ruvalcaba syndromes without PTEN mutations (Yehia_2018) and an individual with sessile/serrated adenoma/polyps of the colon (Sakai_2016). These reports 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. Four ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002500621	SCV002812301	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2021-08-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002515464	SCV004198934	uncertain significance	Familial adenomatous polyposis 1	2023-10-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202229	SCV000257034	uncertain significance	not specified		no assertion criteria provided	research