Submissions for variant NM_000038.6(APC):c.388A>G (p.Ser130Gly)

gnomAD frequency: 0.00010  dbSNP: rs150973053

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122775	SCV000166032	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129715	SCV000184518	likely benign	Hereditary cancer-predisposing syndrome	2018-07-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000211891	SCV000209564	likely benign	not specified	2017-10-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211891	SCV000694040	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.388A>G (p.Ser130Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 253354 control chromosomes. The observed variant frequency is approximately 5 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 benign. c.388A>G has been reported in the literature in individuals. These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with a pathogenic variant has been reported (APC c.3815C>G, p.Ser1272X), providing supporting evidence for a benign role. Nine 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 (benign/likely benign n=7, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000122775	SCV000838062	likely benign	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129715	SCV000902599	likely benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034387	SCV001133330	benign	not provided	2023-03-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155264	SCV001316683	uncertain significance	APC-Associated Polyposis Disorders	2018-01-26	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000034387	SCV001371504	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	APC: BP4, BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034387	SCV002010884	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129715	SCV002536159	benign	Hereditary cancer-predisposing syndrome	2020-07-27	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129715	SCV002819197	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211891	SCV004025027	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034387	SCV000043104	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	RCV000417265	SCV000503532	uncertain significance	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 40 year old with a history of colon cancer diagnosed at age 39 and a family history of colon polyps.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034387	SCV001552159	likely benign	not provided		no assertion criteria provided	clinical testing	The APC p.Ser130Gly variant was identified in 5 of 3188 proband chromosomes (frequency: 0.002) from individuals or families with FAP or atherosclerosis and was present in 1 of 1908 control chromosomes (frequency: 0.0005) from healthy individuals (Cleary 2008, De Rosa 2004, Johnston 2012). The variant was also identified in dbSNP (ID: rs150973053) as "With other allele ", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx and one clinical laboratory; as uncertain significance by two clinical laboratories), MutDB, and in LOVD 3.0 (2x). The variant was not identified in COGR, Cosmic, UMD-LSDB or Zhejiang University databases. The variant was identified in control databases in 85 of 277202 chromosomes at a frequency of 0.0003 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: Other in 4 of 6468 chromosomes (freq: 0.0006), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 4 of 126696 chromosomes (freq: 0.00003), Ashkenazi Jewish in 75 of 10150 chromosomes (freq: 0.007), Finnish in 1 of 25792 chromosomes (freq: 0.00004); it was not observed in the African, East Asian, or South Asian populations. The variant was identified with a co-occurring pathogenic APC variant (c.3815C>G, p.Ser1272*), increasing the likelihood that the p.Ser130Gly variant does not have clinical significance (De Rosa 2004). The p.Ser130 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.
PreventionGenetics, part of Exact Sciences	RCV003944873	SCV004762459	likely benign	APC-related disorder	2020-08-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).