rs2303428 — MSH2

Splice-region variant in MSH2 (c.2006-6T>C) located 6 bases upstream of exon 13 in the mismatch repair gene; the C allele is associated with altered mismatch repair expression and modestly elevated cancer prognosis signals across multiple tumour types; classified benign for Lynch syndrome

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MSH2 rs2303428 — A Splice-Region Variant Shaping Chemotherapy Response

MSH2 (mutS homolog 2)11 MSH2 (mutS homolog 2)
The MSH2 protein forms the MutSα complex with MSH6, which slides along newly replicated DNA scanning for base mismatches and small insertion-deletion loops; when a mismatch is detected, MutSα recruits MutLα (MLH1-PMS2) to initiate repair is the central mismatch recognition protein in the post-replication proofreading machinery. It forms the MutSα complex with MSH6, and together they initiate a repair cascade that culminates in EXO1 (exonuclease 1)22 EXO1 (exonuclease 1)
EXO1 is recruited downstream of MutSα via SHIP-box interaction with MSH2's C-terminal domain; it excises the mismatch-containing DNA strand, creating a gap filled accurately by DNA polymerase excising the error-containing strand. Inherited loss-of-function mutations in MSH2 cause Lynch syndrome — the most common hereditary cancer syndrome — raising lifetime colorectal and endometrial cancer risk to 40–80%.

The rs2303428 variant (c.2006-6T>C) sits six bases upstream of exon 13 in the splice acceptor region of MSH2, a position where changes can subtly influence pre-mRNA processing without abolishing function. It is classified as benign for Lynch syndrome by ClinVar, meaning it does not cause the severe MMR loss seen in pathogenic MSH2 mutations. Yet across multiple cancer-type studies, the C allele consistently correlates with altered tumour behaviour and chemotherapy response — consistent with a quantitative reduction in MSH2 activity rather than a complete loss.

The Mechanism

The c.2006-6T>C change lies within the polypyrimidine tract of the exon 13 splice acceptor site. This position (-6 from the exon boundary) is within the Ensembl Variant Effect Predictor's definition of a splice region variant — not the canonical GT/AG dinucleotides, but still within the regulatory region where U2AF factors bind during spliceosome assembly. A T→C change at this position can alter U2AF65 binding affinity, potentially reducing the efficiency of exon 13 inclusion. If even a fraction of transcripts skip or misprocess exon 13, the result would be a hypomorphic MSH2 protein or reduced total MSH2 expression — consistent with the patterns seen clinically. The CADD score of 16–18 for this variant33 CADD score of 16–18 for this variant
CADD (Combined Annotation Dependent Depletion) scores above 15 indicate the variant is among the top ~3% of deleterious single nucleotide variants genome-wide supports functional relevance above the neutral threshold.

MSH2 is also critical in gametes specifically. MutSα identifies mismatches arising from the high-fidelity but imperfect DNA synthesis during meiotic recombination. During spermatogenesis and oogenesis, MSH2-MSH6 scans the newly formed heteroduplex DNA at recombination intermediates to ensure crossover fidelity. Defective MSH2 activity at this stage would increase the mutation rate transmitted to offspring — the core concern for a gamete-category entry.

The Evidence

The most direct evidence comes from Zhu et al. 201844 Zhu et al. 2018
Rs2303428 of MSH2 is associated with hepatocellular carcinoma prognosis in a Chinese population. DNA Cell Biol 37:596–608, which examined 1,021 HCC cases and 1,021 matched controls and found significantly different genotype distributions at rs2303428 between groups. The CC genotype — the rare homozygous alternate — was paradoxically enriched among cases (14.1% vs 8.2% in controls), while the CT genotype showed elevated HCC risk (OR 1.76, 95% CI 1.20–2.66) relative to TT. In survival analysis, the CC genotype associated with reduced patient survival time (HR 1.27 codominant, HR 1.68 dominant), consistent with altered MMR modulating tumour biology after diagnosis. Gene-environment interaction analyses revealed that the variant amplifies HCC risk in the context of hepatitis B surface antigen positivity.

In gastric cancer, Zhao et al. 201955 Zhao et al. 2019
A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer. Gastric Cancer 22:1121–1129 reported a particularly actionable finding across 760 patients in discovery and validation cohorts: the TC+CC genotype independently predicted worse overall survival in non-cardia gastric cancer (HR 1.54, 95% CI 1.02–2.32), yet TC+CC carriers derived dramatically greater benefit from fluoropyrimidine-based adjuvant chemotherapy (HR 0.14 discovery, HR 0.29 validation) compared to TT patients who showed no chemotherapy benefit. This interaction — where the risk genotype paradoxically improves drug responsiveness — is the hallmark of tumours with partial MMR deficiency, since fluoropyrimidines exploit the replication stress that MMR-impaired cells cannot resolve.

An ovarian cancer study by Si et al. 201966 Si et al. 2019
Genetic polymorphisms in hMSH2 and hMLH1 genes are associated with prognosis in epithelial ovarian cancer patients. Int J Gynecol Cancer 29:1207–1215 found that C allele carriers showed worse progression-free survival during platinum-based chemotherapy (HR 1.41 at 3 years, HR 1.56 at 5 years), with no significant difference in case-control genotype distributions — suggesting the variant influences tumour response rather than cancer initiation.

In metastatic melanoma, Boeckmann et al. 200977 Boeckmann et al. 2009
Effect of DNA repair host factors on temozolomide or dacarbazine melanoma treatment in Caucasians. Pharmacogenet Genomics 19:760–769 found rs2303428 associated with increased hematologic toxicity from alkylating agents alongside a tendency toward better treatment response — a pattern consistent with partial MMR impairment reducing the cell's ability to tolerate temozolomide-induced DNA adducts, enhancing both cytotoxicity and off-target myelosuppression.

The earliest characterisation of this polymorphism as a splice acceptor site variant came from Paz-y-Miño et al. 200388 Paz-y-Miño et al. 2003
Analysis of the polymorphism gIVS12-6T>C in the hMSH2 gene in lymphoma and leukemia. Leuk Lymphoma 44:505–508, which identified the T-to-C change at the intronic -6 position of exon 13 and found it associated with lymphoma (p<0.01) but not leukemia — an early indication of cancer-type specificity.

Practical Actions

The clinically actionable implication of rs2303428 centres on cancer surveillance and chemotherapy pharmacogenomics. The variant is benign for Lynch syndrome and does not warrant the intensive Lynch screening protocols indicated for pathogenic MSH2 mutations. However, C allele carriers show consistent signals across multiple tumour types for altered MMR expression, and the gastric and ovarian cancer data specifically flag a pharmacogenomic interaction with fluoropyrimidines and platinum compounds.

For individuals with a personal or family history of MSH2-associated cancers, this variant adds context to somatic tumour testing: a CC or TC genotype at rs2303428 may contribute to a tumour's MMR profile when evaluated alongside immunohistochemistry. In treatment planning discussions, the chemotherapy-response data — while from relatively small studies — support sharing this genotype information with treating oncologists.

The gamete-DNA-repair relevance is mechanistic rather than directly evidenced: MSH2 functions in meiotic recombination quality control, and any quantitative reduction in MSH2 expression at the splice-region level could affect the fidelity of crossover formation in developing sperm and oocytes. No published studies have directly evaluated rs2303428 effects on gamete mutation rates or meiotic fidelity.

Interactions

The strongest candidate interaction is with rs1799977 in MLH1 (Ile219Val), a fellow MMR gene polymorphism that is similarly benign for Lynch syndrome but shows cancer prognosis associations. Both MSH2 and MLH1 are essential for MutSα-MutLα cascade function; carrying hypomorphic variants in both recognition and mismatch processing steps could additively reduce MMR efficiency below the threshold where tumour microsatellite instability begins to emerge. No published study has formally tested the rs2303428 × rs1799977 combination. MSH2 also interacts with EXO1 (rs1635501) through the well-characterised SHIP-box docking mechanism, and the gamete DNA repair implications of rs2303428 are most relevant in the context of the broader MMR gene network covering MSH2, MLH1, PMS2, MSH6, and EXO1.

Drug Interactions

temozolomide increased_toxicity literature
dacarbazine increased_toxicity literature
fluoropyrimidines reduced_efficacy literature
platinum compounds reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal

Common MSH2 splice-region genotype — no elevated mismatch repair signal at this variant

The TT genotype preserves the native polypyrimidine tract at position -6 of the MSH2 exon 13 splice acceptor site, consistent with normal U2AF65 binding and efficient exon 13 inclusion during pre-mRNA splicing. Multiple cancer prognosis studies — in gastric cancer, hepatocellular carcinoma, and ovarian cancer — have used TT homozygotes as the reference group, finding no significant prognosis modification attributable to this locus. TT carriers in the gastric cancer study (Zhao et al. 2019) specifically did not derive survival benefit from fluoropyrimidine-based adjuvant chemotherapy, consistent with intact MMR and normal tumour response to replication stress.

CT Intermediate

One copy of the C allele — modest mismatch repair signal, relevant for cancer prognosis and chemotherapy context

The CT genotype places one copy of the C allele at the MSH2 intron 12/exon 13 splice acceptor region. The C allele may reduce the efficiency of exon 13 inclusion, potentially generating a small fraction of aberrant transcripts and reducing total MSH2 expression without abolishing it — a quantitative, hypomorphic effect. ClinVar's benign classification for Lynch syndrome means this variant does not cause the complete MSH2 silencing that drives Lynch-associated cancers; the effect is more subtle.

The clinically most actionable finding comes from Zhao et al. 2019 (gastric cancer, 760 patients), where TC+CC genotype carriers derived substantially greater benefit from fluoropyrimidine adjuvant chemotherapy compared to TT patients who showed no benefit. This pharmacogenomic signal has potential relevance for treatment planning discussions.

The variant's relevance in the gamete DNA repair context is mechanistic: MSH2 forms the MutSα complex that corrects mismatches arising during meiotic recombination. Reduced MSH2 expression or efficiency at the splice level could modestly increase the rate of uncorrected mismatches in developing oocytes and sperm, though no published study has directly quantified this effect for rs2303428.

CC High Risk

Homozygous C allele — rarest MSH2 splice-region genotype; consistent signals for altered mismatch repair function across multiple tumour types

CC homozygosity at rs2303428 places both MSH2 intron 12/exon 13 splice acceptor alleles as the C variant. If this position quantitatively reduces exon 13 inclusion efficiency — consistent with its location in the polypyrimidine tract — then CC individuals may have a larger fraction of aberrant MSH2 transcripts than CT heterozygotes, producing a more pronounced reduction in total MSH2 expression. This would manifest as a greater degree of hypomorphic MMR activity: still not the complete silencing of pathogenic Lynch mutations, but enough to alter tumour MSI profiles and chemotherapy sensitivity.

The HCC data (Zhu et al. 2018) show that CC genotype was more frequent among cases (14.1%) than controls (8.2%), and CC individuals who developed HCC had worse prognosis — consistent with a tumour biology shaped by partially impaired MMR. In gene-environment interaction analysis, HBsAg-positive infection amplified the risk associated with this genotype (OR 1.865 for HBsAg interaction), linking defective viral DNA damage processing to hepatocellular transformation risk.

ClinVar's benign classification for Lynch syndrome remains accurate and important: CC at rs2303428 does not indicate Lynch syndrome, does not warrant Lynch screening protocols, and should not be interpreted as a pathogenic mutation in genetic counselling. The clinical significance is in pharmacogenomics and oncology context.