ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6724A>G (p.Ser2242Gly) (rs201375478)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034395 SCV000149023 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted APC c.6724A>G at the cDNA level, p.Ser2242Gly (S2242G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant was observed in at least one individual with colon cancer and in a patient with breast cancer (Tung 2015, Yurgelun 2015, Yurgelun 2017). APC Ser2242Gly was observed at an allele frequency of 0.025% (31/126386) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the basic domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ser2242Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115114 SCV000183843 likely benign Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;No disease association in appropriately sized case-control study(ies)
Invitae RCV000987580 SCV000254030 benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000034395 SCV000333806 uncertain significance not provided 2015-09-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034395 SCV000600137 uncertain significance not provided 2019-11-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515374 SCV000611340 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 RCV000115114 SCV000681821 likely benign Hereditary cancer-predisposing syndrome 2020-06-09 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000664301 SCV000788230 likely benign Familial multiple polyposis syndrome 2018-04-01 criteria provided, single submitter research The APC variant designated as NM_000038.5:c.6724A>G (p.Ser2242Gly) is classified as likely benign. This variant was observed or imputed to be present in two individuals in the same family that are over seventy years old without colorectal cancer, one of whom was documented to not have polyps on colonoscopy. These observations are not consistent with either attenuated or classic familial adenomatous polyposis syndromes. This variant is in ExAC (rs201375478) and is present in approximately 1/3355 individuals of European ancestry, which is greater than the incidence of familial adenomatous polyposis (1/8,000 to 1/10,000). This genomic position is conserved. This variant was also found in co-occurrence with an MSH2 pathogenic mutation. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Mendelics RCV000987580 SCV001136938 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001151801 SCV001312971 likely benign APC-Associated Polyposis Disorders 2017-11-02 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211930 SCV001339031 benign not specified 2021-04-24 criteria provided, single submitter clinical testing Variant summary: APC c.6724A>G (p.Ser2242Gly) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250838 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.0 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 Non-Finnish European origin. c.6724A>G has been reported in the literature in individuals affected with ovarian carcinoma, breast cancer and colorectal cancer (Kanchi_2014, tung_2014, Yurgelun_2015, Yurgelun_2017, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least two co-occurrences with other pathogenic variants have been reported (BRCA2 c.9294C>G, p.Tyr3098Ter; BRCA1 c.5329dupC, p.Gln1777ProfsTer74), providing supporting evidence for a benign role (Tung-2014, Zhunussova_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven 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 citing overlapping evidence utilized in the context of this evaluation (benign, n=1; likely benign, n=4, VUS, n=6). At-least two submitters have re-classified this variant into a benign/likely benign outcome since our previous evaluation. Based on the evidence outlined above, the variant was classified as benign.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000987580 SCV001429678 likely benign Familial adenomatous polyposis 1 2019-02-13 criteria provided, single submitter clinical testing Data included in classification: The variant was observed in 33/141,114 gnomAD controls. (BS1_strong). Missense variant in a gene for which primarily truncating variants are known to cause disease (BP1_sup). Data not included in classification: UK Family 1: Variant found in 2 year old with Gardner fibroma from Finland and his healthy father. In silico tools mixed predictions. Listed on LOVD3 in combination with 2709_2712delCAGA frameshift variant (phase unknown). Multiple recent classifications of variant by US labs as VUS and likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034395 SCV000043134 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353961 SCV000591200 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Ser2242Gly variant has not been previously identified in the literature or by our laboratory. The Ser2242 residue is conserved in mammals, however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Splicing prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a novel splice site in 4 out of 5 different programs, increasing the likelihood that this variant may have a functional consequence, however, this information is not predictive enough to determine outcome and functional studies would be necessary to prove causality. In summary, based on the information above, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as VUS.

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