MSH2 G322D - GET-Evidence


MSH2 G322D

(MSH2 Gly322Asp)

Short summary

Although other variants in this mismatch repair gene are associated with cancer, most publications dismiss this variant as a polymorphism (HapMap allele frequency of 1.6%).

Variant evidence

Disease is associated with disease, disruptive amino acid change (BLOSUM100 = 3), but polyphen and SIFT predicts benign effect.

See Ollila S et al. 2008 (18470917).

Functional 3

Although the analogous variant in yeast appears to cause moderately reduced mismatch repair function, the human variant appears to have no functional impact (at least when the only variant in the protein) — no impact on interaction with MSH6, mismatch binding activities, or mismatch repair activity.

See Drotschmann K et al. 1999 (10469597), Liu WH et al. 2003 (12673796), Ollila S et al. 2008 (18470917).

Case/Control 3

Case/control data supports lack of significant effect.

See Liu T et al. 1998 (10023327), Scartozzi M et al. 2002 (11870161).

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Most studies report no correlation with cancer (Liu et al. 1998, Scartozzi et al. 2002). Although the yeast analog is reported to have impacted function (Drotschmann et al. 1999), Ollila et al. 2008 find no functional difference between this protein and the wild-type when expressed in a human cell system.

Allele frequency

  • A @ chr2:47643457: 1.1% (119/10758) in EVS
  • A @ chr2:47496960: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.1% (119/10758)


Nyström-Lahti M, Wu Y, Moisio AL, Hofstra RM, Osinga J, Mecklin JP, Järvinen HJ, Leisti J, Buys CH, de la Chapelle A, Peltomäki P. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet. 1996 Jun;5(6):763-9. PubMed PMID: 8776590.

In a study of 55 kindreds with hereditary non-polyposis colorectal cancer syndrome the authors report on this variant as a polymorphism because it wasn’t rare (had an allele frequency of at least 4%) and according to them did not cause a “significant amino acid change”.

Liu T, Stathopoulos P, Lindblom P, Rubio C, Wasteson Arver B, Iselius L, Holmberg E, Grönberg H, Lindblom A. MSH2 codon 322 Gly to Asp seems not to confer an increased risk for colorectal cancer susceptibility. Eur J Cancer. 1998 Nov;34(12):1981. PubMed PMID: 10023327.

They found this mutation in 9 of 170 colorectal cancer patients (5.3%) from high risk families and in 6 of those families the variant was shown not to segregate with the disease. The variant was seen in 12 of 192 normal controls and in none of 104 sporadic colorectal cancer cases. Based on this the authors conclude this is a common polymorphism rather than a disease-causing mutation.

Drotschmann K, Clark AB, Kunkel TA. Mutator phenotypes of common polymorphisms and missense mutations in MSH2. Curr Biol. 1999 Aug 26;9(16):907-10. PubMed PMID: 10469597.

These authors report a moderate but significant impact of the analogous G317D mutant in yeast on mutation rates.

Scartozzi M, Bianchi F, Rosati S, Galizia E, Antolini A, Loretelli C, Piga A, Bearzi I, Cellerino R, Porfiri E. Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol. 2002 Mar 1;20(5):1203-8. PubMed PMID: 11870161.

The authors list this as a “known polymorphism” and report an allele frequency of 2.8%.

Liu WH, Kaur M, Makrigiorgos GM. Detection of hotspot mutations and polymorphisms using an enhanced PCR-RFLP approach. Hum Mutat. 2003 May;21(5):535-41. PubMed PMID: 12673796.

Using the quantitative screen they developed, they screened DNA from pooled samples of patients with colorectal carcinoma vs. ethnicity-matched controls (221 Polish patients & controls, 205 US patients & controls). They found this variant was present in 3-5% of individuals, and found no significant difference between patients and matched controls. They confirmed this with sequencing of individual samples, but only report the average numbers (3.4%-4.5% across patients and controls for both groups).

Ollila S, Dermadi Bebek D, Greenblatt M, Nyström M. Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification. Int J Cancer. 2008 Aug 1;123(3):720-4. PubMed PMID: 18470917.

This functional study of the human G322D protein variant (along with the MSH2 N127S) in a human homologous system finds no impact on interaction with MSH6, mismatch binding activities, or mismatch repair activity. They conclude that these are both functionally neutral polymorphisms. They note that SIFT predicts this variant to be “tolerated”, and N127S to be “not tolerated”.




hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr2:47643457


Other external references

  • rs4987188
  • GeneTests records for the MSH2 gene
    Hereditary Non-Polyposis Colon Cancer
    MSH2-Related Hereditary Non-Polyposis Colon Cancer
    MSH2-Related Muir-Torre Syndrome
    MSH2-Related Turcot Syndrome
  • Score: 0.065 (benign)

Other in silico analyses

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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