ClinVar Genomic variation as it relates to human health

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.

Variant summary: APC c.388A>G (p.Ser130Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 253354 control chromosomes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. c.388A>G has been reported in the literature in individuals. These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with a pathogenic variant has been reported (APC c.3815C>G, p.Ser1272X), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=7, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

APC: BP4, BS2

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.

Converted during submission to Uncertain significance.

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).

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 40 year old with a history of colon cancer diagnosed at age 39 and a family history of colon polyps.

The APC p.Ser130Gly variant was identified in 5 of 3188 proband chromosomes (frequency: 0.002) from individuals or families with FAP or atherosclerosis and was present in 1 of 1908 control chromosomes (frequency: 0.0005) from healthy individuals (Cleary 2008, De Rosa 2004, Johnston 2012). The variant was also identified in dbSNP (ID: rs150973053) as "With other allele ", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx and one clinical laboratory; as uncertain significance by two clinical laboratories), MutDB, and in LOVD 3.0 (2x). The variant was not identified in COGR, Cosmic, UMD-LSDB or Zhejiang University databases. The variant was identified in control databases in 85 of 277202 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 6468 chromosomes (freq: 0.0006), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 4 of 126696 chromosomes (freq: 0.00003), Ashkenazi Jewish in 75 of 10150 chromosomes (freq: 0.007), Finnish in 1 of 25792 chromosomes (freq: 0.00004); it was not observed in the African, East Asian, or South Asian populations. The variant was identified with a co-occurring pathogenic APC variant (c.3815C>G, p.Ser1272*), increasing the likelihood that the p.Ser130Gly variant does not have clinical significance (De Rosa 2004). The p.Ser130 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.