ClinVar Genomic variation as it relates to human health

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.

The p.Val461Leu variant in STAT3 is classified as benign because it has been identified in 4.7% (1680/35436) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1

Variant summary: STAT3 c.1381G>C (p.Val461Leu) results in a conservative amino acid change located in the STAT transcription factor, DNA-binding domain (IPR013801) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 251112 control chromosomes, predominantly at a frequency of 0.048 within the Latino subpopulation in the gnomAD database, including 56 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 22000-fold of the estimated maximal expected allele frequency for a pathogenic variant in STAT3 causing Hyper IgE Syndrome phenotype (2.2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Co-occurrences with a pathogenic variant have been reported (STAT3 c.1909G>A, p.V637M; LCA and Sastalla_2017), providing supporting evidence for a benign role. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

The STAT3 p.Val461Leu variant was identified in 4 of 6167 proband chromosomes (frequency: 0.000649) from individuals with suspected hematologic malignancies (Morgan_2017_PMID_29296824). The variant was identified in dbSNP (ID: rs149214040) and ClinVar (classified as likely benign by Illumina for Hyper IgE Syndrome, and as benign by Invitae and ARUP Laboratories). The variant was identified in control databases in 1712 of 268022 chromosomes (56 homozygous) at a frequency of 0.006388 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 1663 of 35104 chromosomes (freq: 0.04737), Other in 42 of 6698 chromosomes (freq: 0.006271), African in 6 of 23606 chromosomes (freq: 0.000254) and European (non-Finnish) in 1 of 117896 chromosomes (freq: 0.000008), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Val461 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.