chr5-112842376-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_000038.6(APC):c.6782C>T(p.Pro2261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2261A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.6782C>T | p.Pro2261Leu | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.6782C>T | p.Pro2261Leu | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251050Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135736
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461802Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14AN XY: 727202
GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74290
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 01, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 17, 2023 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 19, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | 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. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 10, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with mismatch repair (MMR) proficient colon cancer (Pearlman et al., 2016); This variant is associated with the following publications: (PMID: 28873162, 18199528, 27978560) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2021 | 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 3.2e-05 in 251050 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African control individuals is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. 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 (Pearlman_2016, Mandelker_2017). However, these reports do 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. Six ClinVar submitters have assessed the variant since 2014: five have classified it as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at