Submissions for variant NM_000038.6(APC):c.8383G>A (p.Ala2795Thr)

gnomAD frequency: 0.00003  dbSNP: rs369264968

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129383	SCV000184149	benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000657075	SCV000293425	likely benign	not provided	2019-06-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21859464, 25637381, 25559809, 27930734, 18199528)
Counsyl	RCV000410318	SCV000489112	uncertain significance	Familial adenomatous polyposis 1	2016-08-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235766	SCV000538301	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 1 VUS, 1 LB; Identified in one study in a group of patients designated as non-FAP/non-MAP but with 11-99 colorectal adenomas.
Invitae	RCV003315875	SCV000552629	benign	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129383	SCV000902938	likely benign	Hereditary cancer-predisposing syndrome	2016-11-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000410318	SCV001136959	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235766	SCV001361426	uncertain significance	not specified	2020-10-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.8383G>A (p.Ala2795Thr) 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 4.5e-05 in 244578 control chromosomes, predominantly at a frequency of 0.00017 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8383G>A has been reported in the literature in individuals affected with colorectal adenomas (Azzopardi_2008) and colorectal cancer (Chubb_2015). 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. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=6; benign/likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657075	SCV002011079	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410318	SCV002525955	uncertain significance	Familial adenomatous polyposis 1	2022-02-10	criteria provided, single submitter	clinical testing	The APC c.8383G>A (p.Ala2795Thr) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112179674-G-A?dataset=gnomad_r2_1). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with colorectal adenomas (PMID: 18199528,29245953) and colorectal cancer (PMID: 25559809,27302369). This variant is also known as p.Ala2777Thr in the literature. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000129383	SCV002526947	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315875	SCV004018752	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.
CSER _CC_NCGL, University of Washington	RCV000148362	SCV000190052	likely benign	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000657075	SCV001807129	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000657075	SCV001954968	likely benign	not provided		no assertion criteria provided	clinical testing