ClinVar Genomic variation as it relates to human health

The p.Glu1317Gln variant in APC is classified as benign because of lack of conservation and it has been identified in 0.63% (810/128934, 7 homozygotes) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). While variant is present in >12 papers comments suggesting non-pathogenicity. ACMG/AMP Criteria applied: BA1, BP4.

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

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 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, BS1, BS2

Converted during submission to Benign.

The p.Glu1317Gln variant has been previously identified in the literature in 43/4470 (0.010) proband chromosomes and in 26/5002 (0.005) control chromosomes suggesting that this variant is a common variant observed 2 fold higher frequency in probands with attenuated FAP, FAP or multiple adenomas compared to controls (Aceto 2005, Curia 2012, Frayling 1998, Lamlum 2000, Plawski 2008, Azzopardi 2008, Hahnloser 2003, Liang 2013, Abdel-Malak 2015). One study demonstrated loss of heterozygosity in the colon cancer tumors in two individuals from the same family both retaining the variant, however segregation of this variant was not observed in two others with colorectal cancer in the same family and the although the family had multiple members affected with colon cancer their phenotypes were not consistent with FAP (White 1996). Further studies suggested the germline p.Glu1317Gln variant may provide a growth advantage for colorectal tumorigenesis when in combination with other weak mutant APC alleles (Dallosso 2009), but does not account for the occurrence of adenomas (Olschwang 2009 ). While some studies have suggested that the non-synonymous variant p.Glu1317Gln predisposes to multiple colorectal adenomas and CRCs (Lamlum 2000, Hahnloser 2003, Frayling 1998), other studies support a moderate increase in risk of CRC, or none ( Popat 2000, Zauber 2013, Rozek 2006). rnThe variant was identified in dbSNP (ID: rs1801166) “With other allele”, Clinvitae database (classified as benign and conflicting interpretations), COSMIC (in various tissues other than intestinal), InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classifications: benign by Invitae, GeneDX, Emory Genetics, Biesecker Laboratory; uncertain significance by Mayo Clinic and Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine; pathogenic by OMIM and GeneReviews; and classification not provided by ITMI), GeneInsight - COGR database (classified as uncertain significance by a clinical laboratory), and UMD (5x with a “neutral” classification). The variant was identified by our laboratory in 6 individuals with colon or other cancers. The variant was identified in the 1000 Genomes Project in 15 of 5000 chromosomes (frequency: 0.003); HAPMAP-EUR in 6 of 1006 chromosomes (frequency: 0.006), HAPMAP-AFR in 4 of 1322 chromosomes (frequency: 0.003), HAPMAP-SAS in 3 of 978 chromosomes (frequency: 0.003); NHLBI Exome Sequencing Project (ESP) in 80 of 8600 European American (frequency 0.009) and in 28 of 4400 African American alleles (frequency 0.006); the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 500 of 121152 chromosomes (frequency: 0.0.004) (or 382 European individuals, 6 of which are homozygotes, 48 African, 4 Other, 32 Latino, 31 South Asian, 3 European (Finnish), increasing the likelihood this could be a low frequency benign variant. In addition we have observed this variant co-occuring with a known pathogenic variant (APC, c.3183_3187delACAAA) in a patient with confirmed FAP. The p.Glu1317 residue is mostly conserved in mammals with the variant amino acid Gln present in rat, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, increasing the likelihood that this variant does not have clinical significance; however, this information is not predictive enough to rule out 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 benign.