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

gnomAD frequency: 0.00012  dbSNP: rs147655929

Total submissions: 13

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: 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	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198399	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