Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000038.6(APC):c.1965C>T(p.Ile655=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,611,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I655I) has been classified as Benign.
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 5-112837559-C-T is Benign according to our data. Variant chr5-112837559-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.489 with no splicing effect.
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 02, 2024
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Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 30, 2015
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. -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 15, 2016
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not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Jul 31, 2024
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Classic or attenuated familial adenomatous polyposis Benign:1
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Oct 23, 2023
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not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
May 16, 2019
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APC-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Apr 10, 2022
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -