Submissions for variant NM_000038.6(APC):c.3511C>T (p.Arg1171Cys)

gnomAD frequency: 0.00028  dbSNP: rs201830995

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129096	SCV000183807	likely benign	Hereditary cancer-predisposing syndrome	2018-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000590345	SCV000209516	likely benign	not provided	2021-02-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23292937, 26976419, 24599579, 24728327, 25980754, 19642502, 9950360, 25981591, 24163242)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196848	SCV000252918	benign	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239305	SCV000297020	benign	Familial multiple polyposis syndrome	2015-07-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129096	SCV000537434	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590345	SCV000694034	likely benign	not provided	2016-12-16	criteria provided, single submitter	clinical testing	Variant summary: The APC c.3511C>T (p.Arg1171Cys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 38/120476 control chromosomes (1 homozygote), predominantly observed in the Latino subpopulation at a frequency of 0.0014724 (17/11546). This frequency is about 21 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. This variant has been reported in an affected individual with no evidence for causality, and authors classified this variant as polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000590345	SCV000805397	likely benign	not provided	2017-02-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000196848	SCV000838108	likely benign	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590345	SCV000888734	benign	not provided	2017-08-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120025	SCV001156640	likely benign	not specified	2018-09-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129096	SCV002533803	benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120025	SCV002550616	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492414	SCV002798137	likely benign	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590345	SCV003916967	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	APC: BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000196848	SCV004017549	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196848	SCV004931007	likely benign	Familial adenomatous polyposis 1	2024-03-21	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.
ITMI	RCV000120025	SCV000084156	not provided	not specified	2013-09-19	no assertion provided	reference population
3DMed Clinical Laboratory Inc	RCV000677754	SCV000803910	uncertain significance	Carcinoma of colon	2017-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000677754	SCV001549982	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Arg1171Cys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0002) from individuals or families with lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs201830995) as "With Likely benign allele ", ClinVar (classified as benign by Invitae and one clinical laboratory; as likely benign by Ambry Genetics, GeneDx and three clinical laboratories), Cosmic (6x in Stomach, Large intestine, Haematopoietic and lymphoid tissue or Endometrium), MutDB, LOVD 3.0 (4x), and in UMD-LSDB (1x likely neutral), databases. The variant was not identified in COGR, or Zhejiang University, databases. The variant was identified in control databases in 98 of 276674 chromosomes (2 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24006 chromosomes (freq: 0.0002), Other in 11 of 6450 chromosomes (freq: 0.002), Latino in 44 of 34406 chromosomes (freq: 0.001), European in 38 of 126368 chromosomes (freq: 0.0003), and South Asian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Arg1171 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.