Submissions for variant NM_000038.6(APC):c.3161A>C (p.His1054Pro)

gnomAD frequency: 0.00001  dbSNP: rs777538550

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217896	SCV000276699	likely benign	Hereditary cancer-predisposing syndrome	2022-09-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV003650497	SCV000282731	likely benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000657005	SCV000292787	uncertain significance	not provided	2019-01-15	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3161A>C at the cDNA level, p.His1054Pro (H1054P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant was observed in an individual undergoing multigene panel testing for a history of Lynch syndrome associated cancer and/or polyps (Yurgelun 2015). APC His1054Pro was observed at an allele frequency of 0.01% (5/30774) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC His1054Pro is located in the 15-amino acid repeat beta-catenin binding 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 His1054Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000232950	SCV000489062	uncertain significance	Familial adenomatous polyposis 1	2016-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217896	SCV000681581	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1054 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 6/250618 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236039	SCV000731392	uncertain significance	not specified	2017-02-21	criteria provided, single submitter	clinical testing	The p.His1054Pro variant in APC has been reported in one individual with a histo ry of Lynch syndrome-associated cancer and/or polyps who underwent genetic testi ng for Lynch syndrome (Yurgelun 2015) and has also been reported in ClinVar (Va riation ID 232540). In addition, this variant has also been identified in 3/164 56 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs777538550). Computational prediction tools and conservation analysis suggest that the p.His1054Pro variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.His1054Pro variant is uncertain.
Myriad Genetics, Inc.	RCV003316225	SCV004019177	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236039	SCV004024365	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236039	SCV004030033	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: APC c.3161A>C (p.His1054Pro) results in a non-conservative amino acid change in 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 2.4e-05 in 250618 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3161A>C has been reported in the literature as a VUS in an individual undergoing multigene panel testing for Lynch syndrome who had a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis or colorectal cancer risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31422818, 25980754). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=4) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.