Submissions for variant NM_000038.6(APC):c.6782C>T (p.Pro2261Leu)

gnomAD frequency: 0.00021  dbSNP: rs376494248

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130294	SCV000185142	likely benign	Hereditary cancer-predisposing syndrome	2020-01-07	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	RCV000255155	SCV000321404	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 18199528, 35534704, 27978560, 35957908)
Counsyl	RCV000410458	SCV000487801	uncertain significance	Familial adenomatous polyposis 1	2015-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410458	SCV000647667	benign	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130294	SCV000681825	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2261 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 individuals affected with ovarian cancer (PMID: 29684080), unspecified advanced cancer (PMID: 28873162), breast cancer (PMID: 35534704), and colorectal cancer (PMID: 27978560). This variant has been identified in 17/282452 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.
Mendelics	RCV000410458	SCV000838142	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192912	SCV001361369	likely benign	not specified	2024-08-26	criteria provided, single submitter	clinical testing	Variant summary: APC c.6782C>T (p.Pro2261Leu) 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 3.1e-05 in 1613904 control chromosomes, predominantly at a frequency of 0.00065 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). The variant was reported in one individual affected with colorectal cancer, and was also found in a cohort of patients with advanced cancer, who were undergoing multi-gene panel testing (examples: Pearlman_2016, Mandelker_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. The following publications have been ascertained in the context of this evaluation (PMID: 28873162, 27978560). ClinVar contains an entry for this variant (Variation ID: 141681). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255155	SCV002046245	likely benign	not provided	2023-03-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130294	SCV002534496	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410458	SCV004018727	likely benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
All of Us Research Program, National Institutes of Health	RCV003998052	SCV004843460	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2261 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 individuals affected with ovarian cancer (PMID: 29684080), unspecified advanced cancer (PMID: 28873162), breast cancer (PMID: 35534704), and colorectal cancer (PMID: 27978560). This variant has been identified in 17/282452 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.