TABLE 4.
Comparison of minor allele frequencies (MAF) of the eight SNPs utilized for structure–function association analysis among global datasets (https://gnomad.broadinstitute.org).
| Gene | Variant (rsID; AA change) | Percentage of recruited patients with this mutation | gnomAD global MAF (approx.) | South Asian MAF (approx.; gnomAD/1000G/IndiGen) | Cancer/Clinical associations (concise) |
|---|---|---|---|---|---|
| FLT3 | rs1933437 (T227M) | >80% | ∼0.52 (alt allele) – common missense polymorphism in FLT3 | ∼0.65–0.70 (IndiGen ∼0.675; higher than global) | Germline missense in FLT3 (oncogenic kinase). Reported association with sunitinib toxicity and other TKI-related adverse effects; considered a pharmacogenomic variant in Indian cohorts. Additionally, it appears in GWAS signals linked to blood pressure and Tourette’s, but is not a classic high-penetrance cancer driver. |
| XRCC1 | rs1799782 (R194W) | ∼5% | ∼0.05–0.10 globally (low-frequency; varies widely by ancestry, but consistently >0.05 in many datasets) | Variable; ∼0.10–0.25 overall, with reports from ∼0.09 in some North Indian groups to >0.25–0.30 | Base-excision repair variant. Repeatedly studied in lung, colorectal, breast, and head and neck cancers with mixed but suggestive associations with risk. Several studies (including OSCC) indicate impact on response/toxicity to platinum chemo-radiotherapy via altered BER capacity. |
| XRCC1 | rs25487 (Q399R) | >80% | Alt allele AF ∼0.65–0.70 in gnomAD/ExAC (very common) | South Asian MAF typically ∼0.35–0.45 (e.g., A-allele ∼0.42 in the South Indian cohort) | One of the best-studied DNA-repair SNPs. Associated (sometimes inconsistently) with risk of lung, breast, colorectal, ovarian, OSCC, and others and with platinum and cyclophosphamide efficacy/toxicity (e.g., better or worse response depending on the genotype). Frequently appears in pharmacogenomic panels for platinum therapy. |
| DHFR/MSH3 | rs1650697 (I79V) | >80% | Global MAF ≈0.23 (1000G; “T”/variant allele) – common coding variant | SAS MAF ≈0.32 (1000G South Asian; variant allele) | Located in the DHFR/MSH3 locus (5′ UTR in DHFR, missense I79V in MSH3). Acts as an eQTL for MSH3 and DHFR and modifies somatic repeat instability and age at onset in Huntington’s disease and myotonic dystrophy. Additionally, it is studied as a predictor of platinum chemotherapy response via MSH3-mediated mismatch repair. |
| XPC | rs2228000 (A499V) | ∼30% | Global MAF ∼0.20–0.25 (common; gnomAD reports frequency >0.01, Japanese ≈0.23) | Likely in similar range (∼0.20–0.30) in SAS but with inter-study variation (exact gnomAD SAS value depends on release) | NER gene variant. Reported associations with breast cancer, lung cancer, and other solid tumors, especially in Asian cohorts, often in combination with rs2228001. Generally considered a low-penetrance cancer risk modifier affecting nucleotide-excision repair efficiency. |
| XPC | rs2228001 (Q939K) | >80% | Global MAF ∼0.30–0.40; Japanese frequency ∼0.60 for the K allele, indicating it is common worldwide | SAS MAF probably ∼0.30–0.40 (common; precise value varies by cohort) | Another XPC missense variant; associated with risk of prostate cancer, bladder cancer, and other tumors, particularly in Asian populations, and sometimes with altered DNA repair capacity or therapeutic outcomes. Often analyzed in haplotype with rs2228000 in NER-cancer association studies. |
| MUTYH | rs3219489 (Q310H) | ∼40% | gnomAD/ExAC global AF ≈0.25–0.27 (common missense polymorphism) | SAS MAF around 0.30–0.35 in several cohorts (e.g., supplementary tables report ∼0.30–0.38) | Common BER gene variant. ClinVar usually classifies it as benign for classic MUTYH-associated polyposis, but multiple studies link it to modified risk for colorectal, rectal, lung, and other cancers and to outcomes in OSCC chemo-radiotherapy. Best seen as a low-effect risk/response modifier and not a high-penetrance pathogenic mutation. |
| ATM | rs1801516 (D1853N) | ∼20% | gnomAD freq ≈0.11 (alt allele) | South Asian MAF in 1000G ≈ 0.14; some South Asian cohorts (e.g., Sri Lankan) report higher variant allele freq (∼0.42), showing strong population heterogeneity | Key radiogenomic SNP in ATM. Numerous studies/meta-analyses link the A (Asn) allele with increased risk of late radiation toxicity (fibrosis, telangiectasia, pneumonitis, and rectal toxicity) after radiotherapy for breast, lung, prostate, and other cancers. The overall association with cancer risk per se is weak/inconsistent, but some data suggest reduced breast cancer risk for the AA genotype. Additionally, it appears in pharmacogenomic frameworks as a marker of chemo- and radio-toxicity (e.g., with cyclophosphamide/doxorubicin/5-FU). |