MLH1 I219V - GET-Evidence


MLH1 I219V

(MLH1 Ile219Val)

Short summary

Computational evidence, functional assays, and case/control studies suggest this variant is probably benign.

Variant evidence

SIFT 0.46
PolyPhen-2 0.003 (benign)

See Takahashi M et al. 2007 (17510385).


Functional assays in yeast indicate that the MLH1 I219V variant is benign.

See Trojan J et al. 2002 (11781295), Vogelsang M et al. 2009 (19863800).


Case-control studies indicate that there is no association between presence of the MLH1 I219V variant and cancer risk.

See Xu JL et al. 2012 (22631669).

Familial -
Clinical importance

Likely benign

See Trojan J et al. 2002 (11781295), Mei Q et al. 2006 (17074586), Takahashi M et al. 2007 (17510385), An Y et al. 2008 (17870204), Vogelsang M et al. 2009 (19863800), Xu JL et al. 2012 (22631669).


Likely benign

See Trojan J et al. 2002 (11781295), Mei Q et al. 2006 (17074586), Takahashi M et al. 2007 (17510385), An Y et al. 2008 (17870204), Vogelsang M et al. 2009 (19863800), Xu JL et al. 2012 (22631669).


Likely benign

See Trojan J et al. 2002 (11781295), Mei Q et al. 2006 (17074586), Takahashi M et al. 2007 (17510385), An Y et al. 2008 (17870204), Vogelsang M et al. 2009 (19863800), Xu JL et al. 2012 (22631669).



Low clinical importance, Uncertain benign

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

Inheritance pattern


Summary of published research, and additional commentary


Total cases/controls case+ case– control+ control– p-value odds ratio
MLH1-Related Hereditary Non-Polyposis Colon Cancer
16 144 9 141 0.2165 1.741


Allele frequency

  • G @ chr3:37053568: 24.0% (2580/10758) in EVS
  • G @ chr3:37028571: 16.4% (21/128) in GET-Evidence
  • Frequency shown in summary reports: 24.0% (2580/10758)


Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology. 2002 Jan;122(1):211-9. PubMed PMID: 11781295.

In this study, a functional assay was conducted using a human embryonic kidney fibroblast cell line (293T) that lacked MLH1 expression because of the hypermethylation of the promoter region. It was found that PMS2 was also dysfunctional in these cells. Demethylation of the promoter region and subsequent insertion of recombinant MLH1 and PMS2 genes (wild-type) restored full MMR function in these cells. When pathogenic mutations of MLH1 replaced the wild-type MLH1 gene, MMR activity was found to be deficient. When benign polymorphisms including I291V were introduced, MMR activity was normal.

Kondo E, Suzuki H, Horii A, Fukushige S. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003 Jun 15;63(12):3302-8. PubMed PMID: 12810663.


Mei Q, Yan HL, Ding FX, Xue G, Huang JJ, Wang YZ, Sun SH. Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients. Cancer Genet Cytogenet. 2006 Nov;171(1):17-23. PubMed PMID: 17074586.

This study investigated case-control numbers to determine the association of I219V with sporadic colorectal cancer susceptibility in Chinese patients.

Cases/controls case+ case– control+ control– p-value odds ratio
MLH1-Related Hereditary Non-Polyposis Colon Cancer
16 144 9 141 0.2165 1.741


Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007 May 15;67(10):4595-604. PubMed PMID: 17510385.

This study utilized various methods of determining the pathogenicity of several MLH1 variants, including I219V. Yeast assays and in vitro MMR assays were performed to determine the effect of the I219V variant on MMR activity and MLH1 expression. The MLH1 structure of proteins with this variant was also analyzed, and the SIFT program was used to analyze the effect of the mutation on the protein’s function. The I219V variant was found to be associated with medium MMR activity (60.7%), low to medium MLH1 expression (25-75%), and 0.46 SIFT score.

An Y, Jin G, Wang H, Wang Y, Liu H, Li R, Wang H, Qian J, Sun W, Wang Y, Ma H, Miao R, Hu Z, Jin L, Wei Q, Shen H, Huang W, Lu D. Polymorphisms in hMLH1 and risk of early-onset lung cancer in a southeast Chinese population. Lung Cancer. 2008 Feb;59(2):164-70. Epub 2007 Sep 17. PubMed PMID: 17870204.


Vogelsang M, Comino A, Zupanec N, Hudler P, Komel R. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast. BMC Cancer. 2009 Oct 28;9:382. PubMed PMID: 19863800; PubMed Central PMCID: PMC2773791.


Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 05 [updated 2012 Sep 20]. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available from PubMed PMID: 20301390.


Xu JL, Yin ZQ, Huang MD, Wang XF, Gao W, Liu LX, Wang RS, Huang PW, Yin YM, Liu P, Shu YQ. MLH1 polymorphisms and cancer risk: a meta-analysis based on 33 case-control studies. Asian Pac J Cancer Prev. 2012;13(3):901-7. PubMed PMID: 22631669.

This study performed a meta-analysis of 18 case-control studies to determine the association of the MLH1 I219V variant with cancer risk; no association was found.



hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het G @ chr3:37053568


hu0D879F - CGI sample GS00253-DNA_G01_200_37
het G @ chr3:37053568












hu9385BA - CGI sample GS00253-DNA_E01_200_37
het G @ chr3:37053568



huAE6220 - CGI sample GS00253-DNA_H01_200_37
het G @ chr3:37053568




huC30901 - CGI sample GS00253-DNA_B01_200_37
het G @ chr3:37053568


huE80E3D - CGI sample GS00253-DNA_D01_200_37
het G @ chr3:37053568




GS06994 - var-GS06994-1100-36-ASM
het G @ chr3:37028572


GS12004 - var-GS12004-1100-36-ASM
hom G @ chr3:37028572


GS18956 - var-GS18956-1100-36-ASM
het G @ chr3:37028572


GS19669 - var-GS19669-1100-36-ASM
het G @ chr3:37028572


GS19834 - var-GS19834-1100-36-ASM
het G @ chr3:37028572




Other external references

  • rs1799977
  • GeneTests records for the MLH1 gene
    Turcot Syndrome
    Hereditary Non-Polyposis Colon Cancer
    MLH1-Related Hereditary Non-Polyposis Colon Cancer
    MLH1-Related Muir-Torre Syndrome
    MLH1-Related Turcot Syndrome
  • Score: 0.003 (benign)

Other in silico analyses

  • NBLOSUM100 score = –4
  • GET-Evidence autoscore = 3

Edit history

Gene search

"GENE" or "GENE A123C":

Log in