ClinVar Genomic variation as it relates to human health

Variant summary: The variant of interest, c.1211C>T (p.Ser404Phe) alters a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index), although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control datasets of ExAC and gnomAD with an allele frequency of 0.0009281 and 0.0004314 (52/56030 and 106/245718 chrs tested, respectively). These frequencies are significantly greater than the maximum expected allele frequency for a pathogenic STK11 variant of 0.0000063, therefore suggesting the variant of interest is benign. The variant of interest has been reported in multiple affected individuals with varying phenotypic information, including in probands from two unrelated families, where a known pathogenic variants were proven to be causative and segregated with desiase in affected family members (Yurgelun, 2017; Jalth, 2017). In aaddition, multiple clinical labs have classified this variant as "likely benign". Taking together, the variant of interest has been classified as Benign.

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 identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.160% (49 European alleles) and 0.08% in gnomAD (90 European alleles - too high for disease prevalence - highest estimates are 1/60,000). It is classified in ClinVar with 2 stars as Likely benign by 3 submitters (Invitae, Ambry, GeneDx). It has been reported in HGMD in 1 patient with Peutz-Jeghers syndrome and one with renal cell carcinoma. The amino acid is not conserved but no species have a Phe at this position.

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.

Frequently found in patients without signs of PJS; According to the ACMG SVI adaptation criteria we chose this criterion: BS1 (strong benign): AC:77 AF:0.000505747 hom:0 het:77 popmax:NFE popmax AF:0.000867162 popmax AC:59 popmax faf95:0.000689550 significantly greater than the maximum expected allele frequency for a pathogenic STK11 variant of 0.0000063 FLOSSIES num AFR:0 num EUR:10

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.

STK11: BP4

The STK11 p.Ser404Phe variant was identified in 7 of 3890 proband chromosomes (frequency: 0.002) from Lebanese, German, and American individuals or families with breast cancer, hereditary breast cancer, CRC, or Lynch syndrome (Jalkh 2017, Tung 2016, Kraus 2014, Yurgelun 2015). In 1 proband with 3 family members diagnosed with breast cancer, exome sequencing identified the variant co-occurring with 2 other disease-causing mutations (BRCA1 c.G131T, p.C44F and SLX4 c.G421T, p.G141W) (Jalkh 2017). The variant was also identified in dbSNP (ID: rs200078204) “With other allele”, ClinVar (6x as likely benign by GeneDx, Ambry Genetics, Invitae, Illumina, Color Genomics and Quest Diagnostics Nichols Institute San Juan Capistrano and 2x as uncertain significance by EGL Genetic Diagnostics and Laboratory for Molecular Medicine), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB,Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 106 of 245718 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was seen in the following populations: African in 4 of 20584 chromosomes (freq: 0.0002), Other in 3 of 5868 chromosomes (freq: 0.0005), Latino in 7 of 32154 chromosomes (freq: 0.0002), European Non-Finnish in 89 of 109936 chromosomes (freq: 0.0008), and South Asian in 3 of 27996 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser404Phe 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 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 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.

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).