Submissions for variant NM_000038.6(APC):c.7036C>T (p.Pro2346Ser)

gnomAD frequency: 0.00022  dbSNP: rs200756935

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034397	SCV000149027	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 28873162, 22703879, 25203624, 27878467)
Ambry Genetics	RCV000115118	SCV000172875	likely benign	Hereditary cancer-predisposing syndrome	2019-05-02	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.
Invitae	RCV001083312	SCV000219005	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034397	SCV000600143	benign	not provided	2023-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034397	SCV000609172	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	APC: BS1
Fulgent Genetics, Fulgent Genetics	RCV000515182	SCV000611341	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115118	SCV000681842	likely benign	Hereditary cancer-predisposing syndrome	2018-03-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153053	SCV001314301	uncertain significance	APC-Associated Polyposis Disorders	2019-09-09	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120030	SCV001363502	benign	not specified	2019-02-08	criteria provided, single submitter	clinical testing	Variant summary: APC c.7036C>T (p.Pro2346Ser) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 275598 control chromosomes, predominantly at a frequency of 0.0074 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 104 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 Ashkenazi Jewish origin. c.7036C>T has been reported in the literature in individuals affected with different types of cancer, including pancreatic cancer and breast and/or ovarian cancer (Young_2018, Mandelker_2017, Yadav_2017, Maxwell_2016, Grant_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. A co-occurrence with another pathogenic variant has been reported in our internal database (APC c.1690C>T, p.Arg564*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (1x), likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034397	SCV002010860	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120030	SCV002066576	uncertain significance	not specified	2017-12-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115118	SCV002535180	benign	Hereditary cancer-predisposing syndrome	2020-11-11	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115118	SCV002819218	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001083312	SCV005084460	likely benign	Familial adenomatous polyposis 1	2024-04-08	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].
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034397	SCV000043137	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120030	SCV000084161	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001083312	SCV001548588	likely benign	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Pro2346Ser variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0009) from individuals or families with atherosclerosis, unselected for personal or family histories of cancer (Johnston 2012). The variant was also identified in ClinVar (classified as uncertain significance by Quest Diagnostics, Fulgent Genetics and two other submitters; as likely benign by Ambry Genetics, GeneDx and Color; and as benign by Invitae) and LOVD 3.0 (1x as effect unknown/not classified). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 102 of 281270 chromosomes 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: Ashkenazi Jewish in 80 of 10318 chromosomes (freq: 0.008), Other in 6 of 7184 chromosomes (freq: 0.0008), Latino in 4 of 35396 chromosomes (freq: 0.0001), and European (non-Finnish) in 12 of 127880 chromosomes (freq: 0.00009); it was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Pro2346 residue is 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.