Submissions for variant NM_000038.6(APC):c.854A>G (p.Asp285Gly)

gnomAD frequency: 0.00003  dbSNP: rs201093383

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129720	SCV000184524	likely benign	Hereditary cancer-predisposing syndrome	2022-01-04	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.
GeneDx	RCV000211896	SCV000209486	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754)
Invitae	RCV003315881	SCV000282850	uncertain significance	Familial adenomatous polyposis 1	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 285 of the APC protein (p.Asp285Gly). This variant is present in population databases (rs201093383, gnomAD 0.006%). This missense change has been observed in individual(s) with APC-related conditions (PMID: 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 141276). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Counsyl	RCV000229223	SCV000489525	uncertain significance	Familial adenomatous polyposis 1	2016-10-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129720	SCV000681932	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 285 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. This variant has been reported in individuals affected with colorectal cancer (PMID: 28944238, 29212164). This variant has been identified in 8/282502 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211896	SCV001133378	uncertain significance	not provided	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478388	SCV002782199	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2021-12-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315881	SCV004018749	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	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.