ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2204C>T (p.Ala735Val)

gnomAD frequency: 0.00012  dbSNP: rs147655929
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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 RCV000131447 SCV000186431 benign Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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 RCV000034406 SCV000209463 likely benign not provided 2020-02-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23159591, 25980754, 22703879, 26976419, 26845104, 28135145)
Invitae RCV003650358 SCV000252907 benign Familial adenomatous polyposis 1 2024-01-19 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000210149 SCV000266139 likely benign Colorectal cancer, susceptibility to 2019-09-09 criteria provided, single submitter clinical testing The variant occurs at an amino acid position that is evolutionarily conserved, and although it is classified as probably damaging by computer analysis with programs PolyPhen2 and SIFT, no functional studies that describe its impact on protein function have been published. This variant been seen to co-occur with other pathogenic variants in APC (Tung 2015, Kerr 2013). This variant occurs at an allele frequency of 0.002% (gnomAD.broadinstitute.org). There have been no clinical reports on this specific variant suggesting that this variant causes increased cancer risk. ClinVar has an entry for this variant (Variation ID: 41521), which has been classified as likely benign by other laboratories. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded.
Color Diagnostics, LLC DBA Color Health RCV000131447 SCV000681506 likely benign Hereditary cancer-predisposing syndrome 2016-06-24 criteria provided, single submitter clinical testing
Mendelics RCV000198399 SCV000838088 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254627 SCV000918441 benign not specified 2020-11-27 criteria provided, single submitter clinical testing Variant summary: APC c.2204C>T (p.Ala735Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249992 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.2204C>T has been reported in the literature in individuals affected with colorectal cancer (Yurgelun_2015, Yurgelun_2017), breast cancer (Tung_2014, Tung_2016), clinical laboratory APC sequencing cohort (Kerr_2013), patients undergoing multigene panel testing (Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At-least two co-occurrences with other pathogenic variant(s) have been reported (APC c.994C>T, p.Arg332X, Kerr_2013; BRCA2 c.5351dupA, p.Asn1784Lysfs*3, Tung_2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign(n=3)/likely benign(n=2). Based on the evidence outlined above, the variant was re-classified as benign.
CeGaT Center for Human Genetics Tuebingen RCV000034406 SCV001500349 likely benign not provided 2021-01-01 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131447 SCV002535812 likely benign Hereditary cancer-predisposing syndrome 2021-08-03 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034406 SCV004219894 likely benign not provided 2023-02-07 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034406 SCV000043113 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000417343 SCV000503559 likely benign Familial multiple polyposis syndrome 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 58 year old with 5-10 colon polyps and a family history of colon cancer.
3DMed Clinical Laboratory Inc RCV000677783 SCV000803939 uncertain significance Neoplasm of the liver 2017-01-09 no assertion criteria provided clinical testing

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