Accurate classification of<i>MLH1/MSH2</i>missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)

Chao, Elizabeth; Velasquez, Jonathan L.; Witherspoon, Mavee; Rozek, Laura S.; Peel, David; Ng, Pauline C.; Gruber, Stephen B.; Watson, Patrice; Rennert, Gad; Anton‐Culver, Hoda; Lynch, Henry T.; Lipkin, Steven M.

doi:10.1002/humu.20735

Cited by 107 publications

(123 citation statements)

References 56 publications

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“…This group also built a detailed molecular model of the interacting domains of MLH1 and PMS2. Although K618 is often described as being in the PMS2 binding domain (eg, Figure 2 in Chao et al 2008 52 ), this more detailed model shows that position 618 is not directly involved in PMS2 binding. 46 Raevaara et al 45 used a somewhat different experimental design.…”

Section: In Silico Analysismentioning

confidence: 82%

“…Thus, the value obtained for K618A should be interpreted as equivocal, or consistent with a variant of uncertain significance. 52 Functional testing of synthetic or natural gene products has the advantage of not requiring detailed knowledge of family history or characterization of segregation of variants with disease in multiple families. In many cases, assays can be designed to directly assess the effect of specific sequence variants on protein function in vitro.…”

Section: In Silico Analysismentioning

confidence: 99%

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The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG¡GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR ‫؍‬ 2.1, 95% CI ‫؍‬ 1.3 to 3.5; P ‫؍‬ 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was overrepresented in 1742 cases (allele frequency of 0.83) (OR ‫؍‬ 2.0, 95% CI ‫؍‬ 1.2 to 3.2; P ‫؍‬ 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

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Section: In Silico Analysismentioning

confidence: 82%

Section: In Silico Analysismentioning

confidence: 99%

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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“…Chao et al [Chao et al, 2008] have developed a classification system for MMR variants called MAPP-MMR. We used our evaluation set to estimate MAPP-MMR, which has been trained only with 24 pathogenic and 26 neutral variants.…”

Section: Discussionmentioning

confidence: 99%

Classification of mismatch repair gene missense variants with PON-MMR

Ali¹,

Olatubosun²,

Vihinen

2012

Hum. Mutat.

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“…Given their frequent occurrence in MMR genes in (suspected) HNPCC cases (but also in genes involved in other pathologies), a method to determine the functional implications of such mutations is urgently needed. A (Chao, et al, 2008). Small family size and incomplete penetrance often preclude reliable assessment of co-segregation of the variant allele with disease.…”

Section: Introductionmentioning

confidence: 99%

“…Computer algorithms have been developed to estimate the severity of an amino acid substitution based on evolutionary conservation and the physicochemical consequences of the substitution (Chan, et al, 2007;Chao, et al, 2008). However, this approach requires validation by functional studies.…”

Section: Introductionmentioning

confidence: 99%

Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells

et al. 2011

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International audienceMutations in the mismatch repair gene MSH2 underlie hereditary non-polyposis colorectal cancer (Lynch syndrome). While disruptive mutations are overtly pathogenic, the implications of missense mutations found in sporadic colorectal cancer patients or in suspected Lynch syndrome families are often unknown. Adequate genetic counseling of mutation carriers requires phenotypic characterization of the variant allele. We present a novel approach to functionally characterize MSH2 missense mutations. Our approach involves introduction of the mutation into the endogenous gene of murine embryonic stem cells (ESC) by oligonucleotide-directed gene modification, a technique we recently developed in our lab. Subsequently, the mismatch repair capacity of mutant ESC is determined using a set of validated functional assays. We have evaluated four clinically relevant MSH2 variants and found one to completely lack mismatch repair capacity while three behaved as wild-type MSH2 and can therefore be considered as polymorphisms. Our approach contributes to an adequate risk assessment of mismatch repair missense mutations. We have also shown that oligonucleotide-directed gene modification provides a straightforward approach to recreate allelic variants in the endogenous gene in murine embryonic stem cells. This approach can be extended to other hereditary conditions

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Accurate classification ofMLH1/MSH2missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)

Cited by 107 publications

References 56 publications

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Classification of mismatch repair gene missense variants with PON-MMR

Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells

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