Submissions for variant NM_000038.6(APC):c.317G>A (p.Arg106His)

gnomAD frequency: 0.00004  dbSNP: rs201764637

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410470	SCV000489713	uncertain significance	Familial adenomatous polyposis 1	2016-11-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455267	SCV000538303	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with cancer and a clinseq participant
Invitae	RCV000410470	SCV000552490	uncertain significance	Familial adenomatous polyposis 1	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 106 of the APC protein (p.Arg106His). This variant is present in population databases (rs201764637, gnomAD 0.02%). This missense change has been observed in individual(s) with familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 41524). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000034409	SCV000566459	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29422544, 21859464, 22703879, 29413759, 29245953, 18199528)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000455267	SCV000600077	uncertain significance	not specified	2017-06-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565565	SCV000667259	benign	Hereditary cancer-predisposing syndrome	2021-05-14	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.
Color Diagnostics, LLC DBA Color Health	RCV000565565	SCV000681585	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 106 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adenomatous polyposis (PMID: 18199528, 21859464). This variant has also been identified in 13/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455267	SCV000694025	uncertain significance	not specified	2020-10-05	criteria provided, single submitter	clinical testing	Variant summary: APC c.317G>A (p.Arg106His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284804 control chromosomes, predominantly at a frequency of 0.00023 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.317G>A has been reported in the literature in at least an individual affected with familial adenomatous polyposis (Azzopard_2008). This report however, does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659270	SCV000781065	uncertain significance	Familial multiple polyposis syndrome	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034409	SCV000805390	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565565	SCV002533095	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410470	SCV004018794	likely benign	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996161	SCV004837255	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 106 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adenomatous polyposis (PMID: 18199528, 21859464). This variant has also been identified in 13/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034409	SCV000043102	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	RCV000410470	SCV001550131	likely benign	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Arg106His variant was not identified in the literature, nor was it identified in NHLBI GO Exome Sequencing Project, GeneInsight COGR, COSMIC, MutDB, UMD, InSiGHT Colon Cancer Gene Variant Database (LOVD), or the Zhejiang Colon Cancer Database (LOVD). The variant was identified in dbSNP (ID: rs201764637) as “With Uncertain significance allele”, the Clinvitae database and ClinVar database (classification uncertain significance, submitters Counsyl and Biesecker Lab/Human Development Section NIH), the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.002), HAPMAP-SAS in 1 of 978 chromosomes (frequency: 0.001), the genome Aggregation Database (Feb 27, 2017) in 13 of 277212 chromosomes (freq. 0.00005) and the Exome Aggregation Consortium database (August 8th 2016) in 5 of 121334 chromosomes (freq. 0.00004) in the following population: South Asian in 5 of 16512 chromosomes (freq. 0.0003), but was not seen in African, East Asian, European, Latino and Other populations increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In addition the variant was identified in this case as co-occurring with a pathogenic APC variant (c.937_938delGA, p.Glu313AsnfsX13), increasing the likelihood that the variant may not have clinical significance. In addition the variant was identified by our laboratory in a patient with polyposis as co-occurring with a pathogenic APC variant (c.937_938delGA, p.Glu313AsnfsX13), increasing the likelihood that the variant may not have clinical significance . The p.Arg106 residue is conserved in mammals and the variant amino acid His is present in the African clawed frog suggesting that this amino acid substitution may be tolerated. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.