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MSH6

mutS homolog 6, the group of PWWP domain containing|MutS homologs

Basic information

Region (hg38): 2:47695529-47810063

Previous symbols: [ "GTBP" ]

Links

ENSG00000116062 ∙ NCBI:2956 ∙ OMIM:600678 ∙ HGNC:7329 ∙ Uniprot:P52701 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • rhabdomyosarcoma (Moderate), mode of inheritance: AR
  • Lynch syndrome 5 (Strong), mode of inheritance: AD
  • ovarian cancer (Strong), mode of inheritance: AD
  • malignant pancreatic neoplasm (Moderate), mode of inheritance: AD
  • Muir-Torre syndrome (Moderate), mode of inheritance: AD
  • Muir-Torre syndrome (Supportive), mode of inheritance: AD
  • Lynch syndrome (Supportive), mode of inheritance: AD
  • mismatch repair cancer syndrome 1 (Supportive), mode of inheritance: AR
  • Lynch syndrome 5 (Definitive), mode of inheritance: AD
  • mismatch repair cancer syndrome 3 (Definitive), mode of inheritance: AR
  • mismatch repair cancer syndrome 3 (Strong), mode of inheritance: AR
  • Lynch syndrome 5 (Strong), mode of inheritance: AD
  • prostate cancer (Limited), mode of inheritance: AD
  • breast cancer (Limited), mode of inheritance: AD
  • endometrial cancer (Definitive), mode of inheritance: AD
  • mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
  • mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
  • Lynch syndrome (Definitive), mode of inheritance: AD
  • hereditary breast carcinoma (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Colorectal cancer, hereditary nonpolyposis type 5 (Lynch syndrome 5); Mismatch repair cancer syndrome 3; Endometrial cancerAD/AROncologicIn HNPCC, for surveillance, colonoscopy with polyp removal is indicated starting at (whichever is earlier) age 20-25 years or 10 years prior to the earliest familial diagnosis; Prophylactic Hysterectomy with bilateral oophorectomy may be considered after childbearing is completed; For individuals with colon cancer, surgical treatment with full colectomy (and ileorectal anastomosis) is recommended; Cigarette smoking should be avoided; For other tumor types, awareness of cancer risk may allow early diagnosis and treatment, which may reduce morbidity and mortality; Individuals with Mismatch repair cancer syndrome are at risk of multiple types of malignancy, and awareness may allow early detection and managementOncologic9354786; 12732731; 15098177; 15340263; 16000562; 16283678; 17557300; 29345684
Individuals may be at risk for additional types of malignancy

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MSH6 gene.

  • Hereditary cancer-predisposing syndrome (5905 variants)
  • Hereditary nonpolyposis colorectal neoplasms (5617 variants)
  • not provided (1838 variants)
  • Lynch syndrome 5 (1432 variants)
  • not specified (953 variants)
  • Endometrial carcinoma (622 variants)
  • Lynch syndrome (531 variants)
  • Breast and/or ovarian cancer (115 variants)
  • Hereditary nonpolyposis colon cancer (108 variants)
  • Carcinoma of colon (106 variants)
  • Malignant tumor of breast (64 variants)
  • Lynch syndrome 1 (46 variants)
  • MSH6-related condition (44 variants)
  • Lynch-like syndrome (28 variants)
  • Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (23 variants)
  • Endometrial carcinoma;Mismatch repair cancer syndrome 3;Lynch syndrome 5 (22 variants)
  • Gastric cancer (21 variants)
  • Endometrial carcinoma;Mismatch repair cancer syndrome 1;Lynch syndrome 5 (17 variants)
  • Hereditary breast ovarian cancer syndrome (17 variants)
  • Ovarian cancer (15 variants)
  • Inborn genetic diseases (12 variants)
  • Endometrial carcinoma;Lynch syndrome 5;Mismatch repair cancer syndrome 3 (10 variants)
  • Breast carcinoma (9 variants)
  • Mismatch repair cancer syndrome 1;Lynch syndrome 5;Endometrial carcinoma (8 variants)
  • Mismatch repair cancer syndrome 1 (7 variants)
  • Hereditary cancer (6 variants)
  • Colorectal cancer (6 variants)
  • Mismatch repair cancer syndrome 3;Lynch syndrome 5;Endometrial carcinoma (6 variants)
  • Lynch syndrome 5;Endometrial carcinoma;Mismatch repair cancer syndrome 3 (5 variants)
  • Mismatch repair cancer syndrome 3 (5 variants)
  • Mismatch repair cancer syndrome 3;Endometrial carcinoma;Lynch syndrome 5 (5 variants)
  • Lynch syndrome 5;Mismatch repair cancer syndrome 3;Endometrial carcinoma (4 variants)
  • Mismatch repair cancer syndrome 1;Lynch syndrome 5 (4 variants)
  • Neurodevelopmental disorder (4 variants)
  • Endometrial carcinoma;Lynch syndrome 5;Mismatch repair cancer syndrome 1 (3 variants)
  • Mismatch repair cancer syndrome 1;Endometrial carcinoma;Lynch syndrome 5 (3 variants)
  • Hereditary nonpolyposis colorectal carcinoma (2 variants)
  • Lynch syndrome 5;Endometrial carcinoma;Mismatch repair cancer syndrome 1 (2 variants)
  • Uterine corpus cancer (2 variants)
  • Colorectal cancer, non-polyposis (2 variants)
  • Colorectal / endometrial cancer (2 variants)
  • Lynch syndrome 5;Mismatch repair cancer syndrome 1 (2 variants)
  • Neoplasm of ovary (2 variants)
  • Gaucher disease type I (1 variants)
  • Abnormality of the ovary (1 variants)
  • Familial cancer of breast (1 variants)
  • See cases (1 variants)
  • Endometrial carcinoma;Lynch syndrome 5 (1 variants)
  • Colorectal cancer, early onset (1 variants)
  • Papillary carcinoma of the corpus uteri (1 variants)
  • bilateral breast cancer (1 variants)
  • Breast-ovarian cancer, familial, susceptibility to, 1 (1 variants)
  • B Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1 (1 variants)
  • Ovarian carcinoma (1 variants)
  • Familial prostate carcinoma (1 variants)
  • Rhabdomyosarcoma (1 variants)
  • MSH6-related disorders (1 variants)
  • Lynch syndrome;Hereditary nonpolyposis colon cancer (1 variants)
  • Hepatoblastoma (1 variants)
  • Cerebellar medulloblastoma (1 variants)
  • Malignant tumor of prostate (1 variants)
  • Lung sarcomatoid carcinoma (1 variants)
  • Sigmoid colon cancer (1 variants)
  • Lynch syndrome;Mismatch repair cancer syndrome 3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MSH6 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
12
clinvar
1382
clinvar
10
clinvar
 1404
missense
10
clinvar
34
clinvar
3571
clinvar
45
clinvar
10
clinvar
 3670
nonsense
383
clinvar
68
clinvar
16
clinvar
2
clinvar
 469
start loss
3
clinvar
3
clinvar
 6
frameshift
1057
clinvar
154
clinvar
30
clinvar
2
clinvar
 1243
inframe indel
1
clinvar
7
clinvar
171
clinvar
 179
splice donor/acceptor (+/-2bp)
17
clinvar
75
clinvar
4
clinvar
2
clinvar
 98
splice region
?
    Intron variants in splice region, excluding donor/acceptor (+/-2bp)
9
15
82
92
4
 202
non coding
?
    UTR, intron and other, non coding variants
13
clinvar
10
clinvar
110
clinvar
424
clinvar
53
clinvar
 610
Total 1484 351 3914 1857 73

Highest pathogenic variant AF is 0.0000598

Variants in MSH6

This is a list of pathogenic ClinVar variants found in the MSH6 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
2-47782677-T-G Lynch syndrome Benign (Sep 05, 2013)89163
2-47782786-G-A Lynch syndrome Benign (Sep 05, 2013)89162
2-47782889-G-T Likely benign (Apr 16, 2019)1191613
2-47782946-C-T Likely benign (Mar 01, 2019)1205129
2-47783024-C-T Lynch syndrome Benign (Sep 05, 2013)89160
2-47783075-C-T Lynch syndrome Benign (Sep 05, 2013)89158
2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT Hereditary cancer-predisposing syndrome Likely pathogenic (Mar 28, 2020)1765255
2-47783116-G-A Lynch syndrome 5 Likely benign (Jan 13, 2018)336435
2-47783178-G-T Lynch syndrome 5 Uncertain significance (Jan 13, 2018)336436
2-47783183-G-T Lynch syndrome Uncertain significance (Jun 14, 2016)336437
2-47783184-C-G not specified Likely benign (May 19, 2016)386488
2-47783185-T-G Likely benign (Mar 03, 2015)1200848
2-47783186-T-A not specified Likely benign (Mar 31, 2017)508535
2-47783187-T-C not specified Likely benign (Nov 22, 2015)381839
2-47783188-T-G not specified • Lynch syndrome 5 Likely benign (May 28, 2019)385317
2-47783189-A-G not specified Likely benign (Jun 28, 2016)378158
2-47783189-A-T not specified Likely benign (Dec 14, 2016)391966
2-47783190-G-T Uncertain significance (Apr 28, 2015)418952
2-47783193-G-T Lynch syndrome 5 Uncertain significance (Jan 12, 2018)336438
2-47783195-T-C Benign (Mar 19, 2015)1245055
2-47783196-C-G not specified Likely benign (Mar 09, 2016)380202
2-47783197-C-A not specified Likely benign (Oct 27, 2016)379883
2-47783197-C-T Benign (Mar 03, 2015)1221582
2-47783200-C-G not specified Likely benign (Apr 26, 2017)509283
2-47783200-C-T not specified Likely benign (Sep 28, 2017)512429

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
MSH6protein_codingprotein_codingENST00000234420 10114572
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.00003671.0012529404541257480.00181
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-2.789177091.290.00003768907
Missense in Polyphen409375.961.08794749
Synonymous-6.323842561.500.00001272643
Loss of Function4.511853.60.3360.00000342666

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.004750.00469
Ashkenazi Jewish0.001200.00119
East Asian0.003750.00370
Finnish0.00004620.0000462
European (Non-Finnish)0.001860.00180
Middle Eastern0.003750.00370
South Asian0.001150.00114
Other0.002150.00212

dbNSFP

Source: dbNSFP

Function
FUNCTION: Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction. {ECO:0000269|PubMed:10078208, ECO:0000269|PubMed:10660545, ECO:0000269|PubMed:15064730, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:9564049, ECO:0000269|PubMed:9822679, ECO:0000269|PubMed:9822680}.;
Disease
DISEASE: Hereditary non-polyposis colorectal cancer 5 (HNPCC5) [MIM:614350]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:10480359, ECO:0000269|PubMed:10521294, ECO:0000269|PubMed:11586295, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14974087, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22102614, ECO:0000269|PubMed:9354786}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. {ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:14961575}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269|PubMed:17557300}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:10413423, ECO:0000269|PubMed:10537275, ECO:0000269|PubMed:10699937, ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:11470537, ECO:0000269|PubMed:11709755, ECO:0000269|PubMed:11807791, ECO:0000269|PubMed:12522549, ECO:0000269|PubMed:14520694, ECO:0000269|PubMed:14961575, ECO:0000269|PubMed:15483016, ECO:0000269|PubMed:22102614}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Pathway
Mismatch repair - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Signaling Pathways in Glioblastoma;Retinoblastoma (RB) in Cancer;Chromosomal and microsatellite instability in colorectal cancer;Mismatch repair;Mismatch Repair;DNA Repair;Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) (Consensus)

Recessive Scores

pRec
0.777

Intolerance Scores

loftool
0.0212
rvis_EVS
-2.25
rvis_percentile_EVS
1.28

Haploinsufficiency Scores

pHI
0.974
hipred
hipred_score
ghis
0.682

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.827

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Msh6
Phenotype
immune system phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan);

Zebrafish Information Network

Gene name
msh6
Affected structure
whole organism
Phenotype tag
abnormal
Phenotype quality
neoplastic

Gene ontology

Biological process
meiotic mismatch repair;DNA repair;pyrimidine dimer repair;mismatch repair;mitotic G2 DNA damage checkpoint;determination of adult lifespan;intrinsic apoptotic signaling pathway in response to DNA damage;response to UV;viral process;somatic hypermutation of immunoglobulin genes;somatic recombination of immunoglobulin gene segments;negative regulation of DNA endoreduplication;interstrand cross-link repair;replication fork arrest;maintenance of DNA repeat elements;isotype switching;positive regulation of isotype switching;negative regulation of DNA recombination;positive regulation of helicase activity;intrinsic apoptotic signaling pathway
Cellular component
nuclear chromatin;nucleus;nucleoplasm;Golgi apparatus;cytosol;mismatch repair complex;MutSalpha complex;intracellular membrane-bounded organelle
Molecular function
magnesium ion binding;four-way junction DNA binding;chromatin binding;damaged DNA binding;double-stranded DNA binding;protein binding;ATP binding;DNA-dependent ATPase activity;ATPase activity;enzyme binding;mismatched DNA binding;guanine/thymine mispair binding;single guanine insertion binding;single thymine insertion binding;oxidized purine DNA binding;MutLalpha complex binding;methylated histone binding;protein homodimerization activity;ADP binding