All known group A streptococci [GAS] are susceptible to β-lactam antibiotics. We recently identified an invasive GAS (iGAS) variant (/PBP2x-T553K) with unusually high minimum inhibitory concentrations (MICs) for ampicillin and amoxicillin, although clinically susceptible to β-lactams. We aimed to quantitate PBP2x variants, small changes in β-lactam MICs, and lineages within contemporary population-based iGAS. PBP2x substitutions were comprehensively identified among 13,727 iGAS recovered during 2015-2021, in the USA. Isolates were subjected to antimicrobial susceptibility testing employing low range agar diffusion and PBP2x variants were subjected to phylogenetic analyses. Fifty-five variants were defined based upon substitutions within an assigned PBP2x transpeptidase domain. Twenty-nine of these variants, representing 338/13,727 (2.5%) isolates and 16 types, exhibited slightly elevated β-lactam MICs, none of which were above clinical breakpoints. The /PBP2x-T553K variant, comprised of two isolates, displayed the most significant phenotype (ampicillin MIC 0.25 μg/ml) and harbored missense mutations within 3 non-PBP genes with known involvement in antibiotic efflux, membrane insertion of PBP2x, and peptidoglycan remodeling. The proportion of all PBP2x variants with elevated MICs remained stable throughout 2015-2021 (<3.0%). The predominant lineage (/PBP2x-M593T/) was resistant to macrolides/lincosamides and comprised 129/340 (37.9%) of isolates with elevated β-lactam MICs. Continuing β-lactam selective pressure is likely to have selected PBP2x variants that had escaped scrutiny due to MICs that remain below clinical cutoffs. Higher MICs exhibited by /PBP2x-T553K are probably rare due to the requirement of additional mutations. Although elevated β-lactam MICs remain uncommon, /PBP2x-T553K and /PBP2x-M593T/ lineages indicate that antibiotic stewardship and strain monitoring is necessary.