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.

APC: BP4, BP7

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

BA1, BP4, BP7

Variant summary: Variant affects a non-conserved nucleotide and results in a synonymous mutation. Mutation taster predicts disease causing impact while 5/5 in silico tools via Alamut predict no significant effect on normal splicing. It was predominantly observed in the African subcohort of the ExAC project at an allele frequency of 0.538% which exeeds the maximal expected allele frequency of a disease causing APC allele 0.006% indicating a neutral impact. Additionally, clinical diagnostic centers classify variant as Likely Bening/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

The synonymous variant NM_000038.6(APC):c.4893T>C (p.Ser1631=) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 132688 as of 2024-10-03). The variant is observed in one or more well-documented healthy adults. The p.Ser1631= variant is observed in 129/16,256 (0.7936%) alleles from individuals of gnomAD African background in gnomAD. The p.Ser1631= variant is observed in 4/5,008 (0.0799%) alleles from individuals of 1kG All background in 1kG, which is greater than expected for the disorder. The p.Ser1631= variant is not predicted to disrupt an existing splice site. The p.Ser1631= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign.

BA1, BP4, BP7 c.4893T>C, located in exon 16 of the APC gene, is predicted to result in no amino acid change, p.(Ser1631=) (BP7).The variant allele was found in 194/23604 alleles, with a filtering allele frequency of 0,73% at 99% confidence, within the African population in the gnomAD v2.1.1 database (non-cancer data set) (BA1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). This variant has only been reported in the ClinVar database (10x benign, 4x likely benign). Additional information has not been evaluated for this variant. Based on currently available information, the variantc.4893T>C should be considered a benign variant according to ClinGen-APC Guidelines version 1.0.

The APC p.Ser1631= variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs35634377) as "With other allele", and in ClinVar (classified as benign by Invitae, GeneDx, Color and three other submitters; and as likely benign by Ambry Genetics and two other submitters). The variant was identified in control databases in 211 of 276950 chromosomes at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 190 of 24022 chromosomes (freq: 0.008, increasing the likelihood this could be a low frequency benign variant), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 16 of 34412 chromosomes (freq: 0.0005), and European in 1 of 126492 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser1631= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.