APC: BP4, BP7

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.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

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.

Variant summary: The APC c.7821C>T (p.Ser2607Ser) causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 110/120952 (3 homozygotes, 1/1111), predominantly observed in the South Asian, 107/16502 (3 homozygotes, 1/154), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14,0005 (0.0000714). Therefore, suggesting this variant is a common polymorphism found in population(s) of South Asian orign. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although multiple reputable clinical laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.

The APC p.Ser2607= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, UMD-LSDB, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs532235331) “With other allele”, ClinVar (classified benign by Invitae, GeneDx and Quest Diagnostics Nichols Institute San Juan Capistrano; and likely benign by Ambry Genetics, Illumina and Counsyl), Clinvitae (4x), and in control databases in 182 (5 homozygous) of 276188 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Observations by population include African in 1 of 24008 chromosomes (freq. 0.00004), other in 3 of 6444 chromosomes (freq. 0.0005), Latino in 1 of 34310 chromosomes (freq. 0.002), European Non-Finnish in 1 of 126050 chromosomes (freq. 0.000008), East Asian in 2 of 18844 chromosomes (freq: 0.0001), and South Asian in 174 (5 homozygous) of 30656 chromosomes (freq. 0.0064); it was not seen in the Ashkenazi Jewish and European Finnish populations. The p.Ser2607= 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.