ClinVar Miner

Submissions for variant NM_000038.6(APC):c.449A>G (p.Lys150Arg) (rs371085910)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130643 SCV000185522 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-04 criteria provided, single submitter clinical testing Conflicting evidence;RNA Studies;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000656744 SCV000209566 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing This variant is denoted APC c.449A>G at the cDNA level, p.Lys150Arg (K150R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). APC Lys150Arg has been observed in at least two unrelated individuals with multiple colorectal adenomas, at least two individuals with sarcoma, and at least one individual with young-onset breast cancer (Azzopardi 2008, Minde 2011, Zhang 2015, Ballinger 2016, Rummel 2017). APC Lys150Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Lys150Arg is not located in a known functional domain (Azzopardi 2008). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a novel splice site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether APC Lys150Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206082 SCV000260480 uncertain significance Familial adenomatous polyposis 1 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 150 of the APC protein (p.Lys150Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs371085910, ExAC 0.002%). This variant has been observed in individuals with clinical features of familial adenomatous polyposis (PMID: 18199528, Invitae). However, in one of these individuals a pathogenic allele was also identified in APC, which suggests that this c.449A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 141928). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000130643 SCV000686977 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211892 SCV000711457 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing The p.Lys150Arg variant in APC has been reported in 2 individuals with colorecta l adenomas (Azzopardi 2008). This variant has been identified in 1/66536 Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit; dbSNP rs371085910). Computational prediction tools and conservation ana lysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys150Arg variant is uncertain.
Counsyl RCV000206082 SCV000785842 uncertain significance Familial adenomatous polyposis 1 2017-12-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656744 SCV000805411 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211892 SCV000918433 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: APC c.449A>G (p.Lys150Arg) results in a 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 2.2e-05 in 273686 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.449A>G has been reported in the literature in individuals affected with breast cancer and colon colorectal adenomas (Azzopardi_2008, Rummel_2017). These reports do not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148370 SCV000190062 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research
True Health Diagnostics RCV000130643 SCV000693483 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-25 no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000760991 SCV000890906 uncertain significance Alveolar rhabdomyosarcoma (disease); Sarcoma 2017-04-04 no assertion criteria provided clinical testing

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