Submissions for variant NM_000038.6(APC):c.3479C>A (p.Thr1160Lys)

gnomAD frequency: 0.00017  dbSNP: rs201004111

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130655	SCV000185540	likely benign	Hereditary cancer-predisposing syndrome	2018-11-29	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	RCV000034385	SCV000209515	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of colorectal adenomas or colorectal cancer (Azzopardi et al., 2008; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 33918692, Biswas2021[abstract], 22703879, 25637381, 21859464, 18199528, 27150160, 27600092, 29212164, 28873162, 30709382, 35128723, 26580448, 35145771)
Invitae	RCV003534315	SCV000259359	likely benign	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000204291	SCV000487797	uncertain significance	Familial adenomatous polyposis 1	2015-11-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235094	SCV000538297	uncertain significance	not specified	2017-01-24	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: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034385	SCV000600083	likely benign	not provided	2023-08-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130655	SCV000681610	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 1160 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual each affected with familial adenomatous polyposis (PMID: 18199528), colorectal cancer (PMID: 29212164), serrated polyposis syndrome (PMID: 35128723), breast cancer (PMID: 29684080) and in an individual(s) with an unspecified cancer (PMID: 28873162). This variant has also been observed in multiple individuals in the general population who were selected for phenotypes not directly related to cancer (PMID: 22703879, 25637381). This variant has been identified in 32/282180 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	RCV000235094	SCV000916470	likely benign	not specified	2022-05-08	criteria provided, single submitter	clinical testing	Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in the one of the 15 residue repeat domains (IPR009240) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250788 control chromosomes, predominantly at a frequency of 0.00021 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 3 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. c.3479C>A has been reported in the literature in individuals affected with non-FAP non-MAP colorectal adenomas (example, Azzopardi 2008), in a family with colorectal cancer without polyps (example, Raskin 2017) and as a VUS in settings of multigene panel testing performed in an individual with Serrated Polyposis Syndrome (SPS) (example, Murphy_2022). 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. Eight 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 (likely benign/benign, n=3; VUS, n=5). At-least one submitter reports an unspecified pathogenic co-occurrence within the same gene as a basis of a likely benign outcome and some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000204291	SCV001136903	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130655	SCV002533780	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000034385	SCV003826838	uncertain significance	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204291	SCV004018831	likely benign	Familial adenomatous polyposis 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003407396	SCV004115157	uncertain significance	APC-related condition	2023-10-02	criteria provided, single submitter	clinical testing	The APC c.3479C>A variant is predicted to result in the amino acid substitution p.Thr1160Lys. This variant was reported in multiple individuals with colorectal adenoma, but was also present in one unaffected 48 year old family member (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde et al. 2011. PubMed ID: 21859464; Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174770-C-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/41503/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034385	SCV004227110	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	BS1
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034385	SCV000043123	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148371	SCV000190064	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research