Submissions for variant NM_000038.6(APC):c.5528C>T (p.Pro1843Leu)

gnomAD frequency: 0.00004  dbSNP: rs368080169

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679068	SCV000149013	uncertain significance	not provided	2023-11-22	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 or family history of a Lynch syndrome-associated cancer, colon polyps, and/or breast and ovarian cancer (PMID: 16650078, 25980754, 28828701); This variant is associated with the following publications: (PMID: 25980754, 16650078, 21859464, 25637381, 31159747, 18199528, 26508446, 28828701)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148372	SCV000254025	likely benign	Familial adenomatous polyposis 1	2024-01-15	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202997	SCV000257787	uncertain significance	Familial multiple polyposis syndrome	2015-02-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000115104	SCV000538302	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: Only reported in 1 or 2 probands; ClinVar: 4 VUS
Ambry Genetics	RCV000572635	SCV000667335	benign	Hereditary cancer-predisposing syndrome	2021-03-31	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.
Color Diagnostics, LLC DBA Color Health	RCV000572635	SCV000681748	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1843 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 an individual affected with breast cancer (PMID: 28828701), adenomatous polyposis and colon cancer (PMID: 16650078), colorectal cancer (PMID: 26508446), and another individual with a monoallelic pathogenic MUTYH variant who is suspected of Lynch syndrome (PMID: 25980754). This variant has also been identified in 21/251006 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.
Eurofins Ntd Llc (ga)	RCV000679068	SCV000702013	uncertain significance	not provided	2016-10-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000148372	SCV000785043	uncertain significance	Familial adenomatous polyposis 1	2017-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679068	SCV000805436	uncertain significance	not provided	2017-11-15	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000572635	SCV000821817	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000115104	SCV000916458	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: APC c.5528C>T (p.Pro1843Leu) results in a non-conservative amino acid change in 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 8.4e-05 in 251106 control chromosomes, predominantly at a frequency of 0.00019 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), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5528C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, Colorectal cancer, Lynch syndrome and personal or family history of HBOC, all without strong evidence for causality (e.g. Hadjisavvas_2006, Yurgelun_2015, Lupini_2015, Zidan_2017, Schubert_2019, Tsaousis_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 31937788, 25637381, 16650078, 30426508, 31159747, 28828701, 26508446). ClinVar contains an entry for this variant (Variation ID: 127306). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679068	SCV002010869	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315229	SCV004012961	uncertain significance	Diffuse midline glioma, H3 K27-altered	2022-12-09	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000148372	SCV004018809	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000572635	SCV005045415	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115104	SCV005090706	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148372	SCV000190066	uncertain significance	Familial adenomatous polyposis 1	2014-06-01	no assertion criteria provided	research