Submissions for variant NM_000038.6(APC):c.3625G>A (p.Glu1209Lys)

gnomAD frequency: 0.00005  dbSNP: rs201185479

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130302	SCV000185151	likely benign	Hereditary cancer-predisposing syndrome	2018-06-25	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.
Invitae	RCV003743588	SCV000254009	likely benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000236652	SCV000293890	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 29058119, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000130302	SCV000681619	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1209 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 colorectal cancer (PMID: 28135145). This variant has been identified in 12/281956 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.
Counsyl	RCV000198440	SCV000785837	uncertain significance	Familial adenomatous polyposis 1	2017-12-18	criteria provided, single submitter	clinical testing
Mendelics	RCV003492599	SCV000838109	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001154640	SCV001316018	uncertain significance	APC-Associated Polyposis Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000236652	SCV002563848	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	APC: BP1
Myriad Genetics, Inc.	RCV003315888	SCV004018716	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	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	RCV003479014	SCV004222722	likely benign	not specified	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.3625G>A (p.Glu1209Lys) 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 allele was found at a frequency of 0.00011 in 1614066 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3625G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=3, VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign.