Submissions for variant NM_000038.6(APC):c.5801C>T (p.Pro1934Leu)

gnomAD frequency: 0.00012  dbSNP: rs587780600

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122787	SCV000166044	likely benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000656747	SCV000209534	likely benign	not provided	2020-03-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18199528, 27150160, 26580448, 21901162, 25925381, 21859464, 26845104, 28873162, 29684080, 29641532)
Ambry Genetics	RCV000159562	SCV000213581	benign	Hereditary cancer-predisposing syndrome	2020-06-12	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
CSER _CC_NCGL, University of Washington	RCV000210900	SCV000264591	uncertain significance	Familial multiple polyposis syndrome	2015-12-01	criteria provided, single submitter	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210078	SCV000266143	uncertain significance	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211923	SCV000538300	uncertain significance	not specified	2016-03-31	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: 1 report in probands; ExAC: 6/11510 Latino; ClinVar: 3 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656747	SCV000600120	likely benign	not provided	2023-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159562	SCV000681763	likely benign	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000122787	SCV000838137	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764567	SCV000895655	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211923	SCV000918453	benign	not specified	2021-04-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.5801C>T (p.Pro1934Leu) results in a non-conservative amino acid change located in the 20-amino acid beta-catenin down-regulating repeats (20AAR) (Azzopardi_APC_Cancer Res_2008) 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 0.00014 in 249974 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 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 Latino origin. c.5801C>T has been reported in the literature in individuals affected with multiple colorectal adenomas (Azzopardi 2008), and in other patients with various tumor phenotypes (Zhang 2015, Shirts 2015, Pritchard 2018). In one of these reports, this variant occurred in the germline of a patient with hypodiploid ALL and is unlikely to have been the primary causative lesion associated with the patient presentation (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Azzopardi 2008). Eleven 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 (benign/likely benign, n=2; VUS, n=9). At-least two additional submitters have re-classified this variant as likely benign/benign since our previous evaluation. One submitter cites an unspecified co-occurrence with a mutation in another gene that clearly explains a proband's phenotype. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001155575	SCV001317012	uncertain significance	APC-Associated Polyposis Disorders	2019-03-08	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000211923	SCV002066674	uncertain significance	not specified	2020-11-12	criteria provided, single submitter	clinical testing	This sequence change has been described in the gnomAD database with a global population frequency of 0.014% and 0.04% in the Latino sub population (dbSNP rs587780600). This sequence change has been reported in some patients with colorectal adenoma, one patient with adenomatous colorectal polyps and one patient with bilateral breast cancer (PMIDs: 21859464, 18199528 and 26845104). There is some experimental evidence that does not demonstrate damaging effect for this variant (PMID 18199528). The p.Pro1934Leu change affects a highly conserved amino acid residue located in the 20-amino acid repeat beta-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (PMID 18199528). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro1934Leu substitution. Due to these contrasting evidences, the clinical significance of the p.Pro1934Leu change remains unknown at this time.
CeGaT Center for Human Genetics Tuebingen	RCV000656747	SCV002497339	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	APC: BP1
Sema4, Sema4	RCV000159562	SCV002528010	likely benign	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003398739	SCV004110069	uncertain significance	APC-related disorder	2023-06-22	criteria provided, single submitter	clinical testing	The APC c.5801C>T variant is predicted to result in the amino acid substitution p.Pro1934Leu. This variant has been observed in individuals with colorectal adenomas, extrauterine Müllerian carcinoma, bilateral breast cancer, pediatric-onset hypodiploid acute lymphocytic leukemia, and advanced cancer (Azzopardi et al. 2008. PubMed ID: 18199528; Minde et al. 2011. PubMed ID: 21859464; Table S2, Rittenhouse et al. 2016. PubMed ID: 27150160; Shirts et al. 2016. PubMed ID: 26845104; Table S41, Zhang et al. 2015. PubMed ID: 26580448; eTable, Mandelker et al. 2017. PubMed ID: 28873162). It has also been reported in an endometrial carcinoma specimen from The Cancer Genome Atlas (TGCA; Table S9, Yehia et al. 2018. PubMed ID: 29684080) and a lung tumor specimen (Table S9, Sample LU-114, Hovelson et al. 2015. PubMed ID: 25925381). This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112177092-C-T) and has conflicting interpretations ranging from benign to uncertain by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/135709/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV000122787	SCV005084443	likely benign	Familial adenomatous polyposis 1	2024-04-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.