ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3511C>T (p.Arg1171Cys) (rs201830995)

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Total submissions: 13
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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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
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)
Invitae RCV000196848 SCV000252918 benign Familial adenomatous polyposis 1 2020-12-04 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 Health, Inc 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,PreventionGenetics 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
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.

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