Gastric cancer: genes and variants

Genes linked to Gastric cancer

• MUTYH: Adenine DNA glycosylase

  It removes adenines incorrectly paired with oxidized guanine, preventing characteristic G:C-to-T:A mutations during base-excision repair. Biallelic loss-of-function variants cause MUTYH-associated polyposis and substantially increase colorectal-cancer risk.

  11 disease-causing and 75 uncertain variants in MUTYH are linked to Gastric cancer.

• FGFR2: Fibroblast growth factor receptor 2

  Its fibroblast-growth-factor signaling regulates proliferation, differentiation, and developmental patterning across multiple tissues. Germline activating variants cause several craniosynostosis syndromes, while somatic mutations, amplification, or fusions can drive cancer.

  2 disease-causing and 5 uncertain variants in FGFR2 are linked to Gastric cancer.

• ERBB2: Receptor tyrosine-protein kinase erbB-2

  ERBB2, also called HER2, is a cell-surface receptor tyrosine kinase that works with other ERBB receptors to transmit growth signals. It helps organize signaling and cytoskeletal responses, and abnormal ERBB2 activity is a major feature of several cancers.

  1 disease-causing and 34 uncertain variants in ERBB2 are linked to Gastric cancer.

• EPCAM: Epithelial cell adhesion molecule

  It supports epithelial organization and signaling at cell-cell interfaces. Deletions extending through its 3-prime end can silence neighboring MSH2 and cause Lynch syndrome, while biallelic loss-of-function variants cause congenital tufting enteropathy.

  1 disease-causing and 0 uncertain variants in EPCAM are linked to Gastric cancer.

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  1 disease-causing and 1 uncertain variants in PIK3CA are linked to Gastric cancer.

• PALB2: Partner and localizer of BRCA2

  It physically links BRCA1 and BRCA2 and helps recruit BRCA2-RAD51 repair machinery to DNA double-strand breaks. Heterozygous loss-of-function variants substantially increase breast and pancreatic cancer risk, while biallelic variants cause Fanconi anemia subtype N.

  1 disease-causing and 0 uncertain variants in PALB2 are linked to Gastric cancer.

• TP53: Cellular tumor antigen p53

  It coordinates transcriptional responses to DNA damage and other cellular stresses, promoting cell-cycle arrest, senescence, DNA repair, or apoptosis when appropriate. Loss of this tumor-suppressive control is one of the most common events in cancer, while germline pathogenic variants cause Li-Fraumeni syndrome.

  1 disease-causing and 0 uncertain variants in TP53 are linked to Gastric cancer.

• APC: Adenomatous polyposis coli protein

  A tumor-suppressor protein that promotes the removal of beta-catenin and helps keep Wnt signaling under control. It also organizes microtubules and actin in the cell, and inherited APC disruption is strongly associated with familial adenomatous polyposis and colorectal tumor risk.

  0 disease-causing and 20 uncertain variants in APC are linked to Gastric cancer.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  0 disease-causing and 1 uncertain variants in KRAS are linked to Gastric cancer.

• RAD51D: DNA repair protein RAD51 homolog 4

  It supports RAD51-mediated homologous recombination and chromosome stability after DNA double-strand breaks. Heterozygous loss-of-function variants confer substantial ovarian-cancer risk and a more moderate increase in breast-cancer susceptibility.

  0 disease-causing and 0 uncertain variants in RAD51D are linked to Gastric cancer.

• ATM: Serine-protein kinase ATM

  It is activated by DNA double-strand breaks and coordinates checkpoint arrest, repair, and apoptosis through phosphorylation of numerous targets. Biallelic loss causes ataxia-telangiectasia, while heterozygous pathogenic variants increase susceptibility to several cancers.

  0 disease-causing and 0 uncertain variants in ATM are linked to Gastric cancer.

• BARD1: BRCA1-associated RING domain protein 1

  It forms a heterodimer with BRCA1 that supports homologous recombination, DNA-damage signaling, and ubiquitin-dependent regulation at damaged chromatin. Germline loss-of-function variants confer increased breast-cancer susceptibility, particularly for some aggressive subtypes.

  0 disease-causing and 0 uncertain variants in BARD1 are linked to Gastric cancer.

• BRIP1: Fanconi anemia group J protein

  It unwinds DNA structures and works with BRCA1 and the Fanconi-anemia pathway to repair damaged replication intermediates and interstrand crosslinks. Biallelic loss causes Fanconi anemia group J, while heterozygous loss-of-function variants increase ovarian-cancer risk.

  0 disease-causing and 0 uncertain variants in BRIP1 are linked to Gastric cancer.

• CHEK2: Serine/threonine-protein kinase Chk2

  It propagates DNA-damage checkpoint signals to proteins controlling cell-cycle arrest, repair, and apoptosis. Germline loss-of-function variants confer moderate cancer susceptibility, especially for breast cancer, while risk estimates depend on the specific allele and family context.

  0 disease-causing and 0 uncertain variants in CHEK2 are linked to Gastric cancer.

• DPYD: Dihydropyrimidine dehydrogenase [NADP(+)]

  It performs the rate-limiting catabolic step for uracil and thymine and clears most administered fluoropyrimidine drug. Reduced activity can cause dihydropyrimidine dehydrogenase deficiency and markedly increases the risk of severe 5-fluorouracil or capecitabine toxicity.

  0 disease-causing and 0 uncertain variants in DPYD are linked to Gastric cancer.

• MLH1: DNA mismatch repair protein Mlh1

  The protein partners with PMS2 to form MutL alpha, a core complex in post-replicative DNA mismatch repair. By helping correct copying errors in DNA, MLH1 protects genome stability, and inherited MLH1 variants are a major cause of Lynch syndrome.

  0 disease-causing and 0 uncertain variants in MLH1 are linked to Gastric cancer.

• PDCD1: Programmed cell death protein 1

  PDCD1 is an inhibitory receptor on activated T cells that binds PD-L1 and PD-L2. Its signaling helps maintain immune tolerance by restraining T-cell activation, making the protein important in autoimmunity and cancer immunotherapy.

  0 disease-causing and 0 uncertain variants in PDCD1 are linked to Gastric cancer.

• PMS2: Mismatch repair endonuclease PMS2

  Together with MLH1, it provides endonuclease activity needed to complete DNA mismatch repair after replication errors are recognized. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants cause constitutional mismatch-repair deficiency.

  0 disease-causing and 0 uncertain variants in PMS2 are linked to Gastric cancer.

• RAD51C: DNA repair protein RAD51 homolog 3

  It participates in RAD51-paralog complexes that promote homologous-recombination repair and restart damaged replication forks. Heterozygous loss-of-function variants increase ovarian and breast-cancer risk, while biallelic variants can cause Fanconi anemia.

  0 disease-causing and 0 uncertain variants in RAD51C are linked to Gastric cancer.

• TUBA1A: Tubulin alpha-1A chain

  An alpha-tubulin chain that pairs with beta-tubulin to build microtubules. Microtubules provide tracks for transport and help shape dividing and migrating cells, making TUBA1A especially important for fetal brain development.

  0 disease-causing and 0 uncertain variants in TUBA1A are linked to Gastric cancer.

• MSH6: DNA mismatch repair protein Msh6

  Together with MSH2, it recognizes single-base mismatches and small insertion-deletion loops during DNA replication and initiates mismatch repair. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants can cause constitutional mismatch-repair deficiency.

  1 disease-causing and 0 uncertain variants in MSH6 are linked to Gastric cancer.

Weakly linked (only a few uncertain records): IL1RN, ATP6V1A, FAT2 and MCM5.

Known disease-causing variants in Gastric cancer

Which prediction tools work for Gastric cancer

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 80 out of 100
• SIFT: 78 out of 100
• MetaLR: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 71 out of 100

Same protein, different disease

• Familial adenomatous polyposis is also caused by MUTYH variants; they fall mostly in different places as the Gastric cancer variants (27 disease-causing).
• FGFR2-related craniosynostosis is also caused by FGFR2 variants; they fall mostly in different places as the Gastric cancer variants (54 disease-causing).
• Crouzon syndrome is also caused by FGFR2 variants; they fall mostly in different places as the Gastric cancer variants (22 disease-causing).
• Pfeiffer syndrome is also caused by FGFR2 variants; they fall mostly in different places as the Gastric cancer variants (13 disease-causing).
• Acrocephalosyndactyly type I is also caused by FGFR2 variants; they fall mostly in different places as the Gastric cancer variants (6 disease-causing).
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis is also caused by FGFR2 variants; they fall mostly in different places as the Gastric cancer variants (5 disease-causing).
• Malignant tumor of urinary bladder is also caused by ERBB2 variants; they fall mostly in different places as the Gastric cancer variants (6 disease-causing).
• Lung adenocarcinoma is also caused by ERBB2 variants; they fall mostly in different places as the Gastric cancer variants (3 disease-causing).
• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Gastric cancer variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Gastric cancer variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Gastric cancer variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall mostly in different places as the Gastric cancer variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Gastric cancer variants (4 disease-causing).

Diseases related to Gastric cancer

• Colorectal cancer, also linked to APC, ATM, CHEK2, ERBB2 and 7 more
• Ovarian cancer, also linked to APC, ATM, BARD1, BRIP1 and 6 more
• Hereditary breast ovarian cancer syndrome, also linked to ATM, BARD1, BRIP1, CHEK2 and 6 more
• Familial cancer of breast, also linked to ATM, BARD1, BRIP1, CHEK2 and 5 more
• Breast and/or ovarian cancer, also linked to BARD1, BRIP1, CHEK2, MLH1 and 5 more
• Non-small cell lung carcinoma, also linked to ERBB2, KRAS, PDCD1, PIK3CA and 1 more
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to BRIP1, PALB2, RAD51C, RAD51D and 1 more
• Lynch syndrome, also linked to EPCAM, MLH1, MSH6 and PMS2
• Hereditary nonpolyposis colon cancer, also linked to CHEK2, MLH1, MSH6 and PMS2
• Ovarian neoplasm, also linked to BRIP1, ERBB2, PIK3CA and TP53
• Lung cancer, also linked to ERBB2, KRAS, PDCD1 and PIK3CA
• Endometrial carcinoma, also linked to MLH1, MSH6, PIK3CA and PMS2

Frequently asked questions

Which genes are linked to Gastric cancer?

In CATVariant, Gastric cancer is linked to 21 analyzed proteins: MUTYH (Adenine DNA glycosylase), FGFR2 (Fibroblast growth factor receptor 2), ERBB2 (Receptor tyrosine-protein kinase erbB-2), EPCAM (Epithelial cell adhesion molecule), PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform), PALB2 (Partner and localizer of BRCA2) and 15 more.

How many genetic variants are linked to Gastric cancer?

191 variants: 19 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 139 are of uncertain significance or have conflicting reports.

Which uncertain variants in Gastric cancer look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Gastric cancer?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.80, based on 14 disease-causing and 399 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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