ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7036C>T (p.Pro2346Ser) (rs200756935)

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Total submissions: 12
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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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV001083312 SCV000219005 benign Familial adenomatous polyposis 1 2020-12-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034397 SCV000600143 benign not provided 2019-04-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034397 SCV000609172 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
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 Health, Inc RCV000115118 SCV000681842 likely benign Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
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.

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