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P003 MLH1/MSH2

SALSA MLPA Probemix P003 MLH1/MSH2 detects copy number variations in the MLH1, MSH2 and EPCAM genes and a recurrent 10 Mb inversion in chromosome arm 2p.

Specifications

Contents: 50 MLPA probes, including 19 probes for MLH1, 18 probes for MSH2, 2 probes for EPCAM and 2 probes for a recurrent 10 Mb inversion that disrupts MSH2.

Tissue: genomic DNA isolated from human peripheral whole blood.

Application: Lynch syndrome (LS).

IVDR certified and registered for in vitro diagnostic (IVD) use in selected territories.

Copy number variations of MLH1 and MSH2 identified with P003 MLH1/MSH2 can be confirmed with P248 MLH1-MSH2 Confirmation.

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List Prices Documentation Compare Lynch Syndrome Products

Key related products

D001 Hereditary Cancer Panel 1

Targets 28 genes involved in hereditary predisposition to cancer, including MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH.

P248 MLH1-MSH2 Confirmation

Targets MLH1 and MSH2, involved in Lynch syndrome. Can be used to confirm P003 MLH1/MSH2 results.

P072 MSH6-MUTYH

Targets MSH6 and EPCAM/MSH2, involved in Lynch syndrome, and MUTYH, involved in MUTYH-associated polyposis (MAP).

ME011 Mismatch Repair Genes

Methylation status of the promoter regions of MLH1, MSH2, MSH6, and PMS2. Also targets EPCAM copy number and the BRAF p.V600E mutation.

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This product has recently been CE-marked for in vitro diagnostic (IVD) use under the In Vitro Diagnostic Regulation (IVDR; EU 2017/746), which replaces the former CE-marking under the IVD Directive (IVDD; Directive 98/79/EC). This update was accompanied by a change in the intended purpose and a change in format of the product description. Some information can now be found in a different location (more information).

Compare Lynch syndrome and polyposis syndrome products from MRC Holland.

Intended purpose

The SALSA MLPA Probemix P003 MLH1/MSH2 is an in vitro diagnostic (IVD) semi-quantitative manual assay for the detection of deletions or duplications in the MLH1 and MSH2 genes and deletions of exon 9 in the EPCAM gene, as well as a recurrent 10 Mb inversion on chromosome arm 2p which disrupts the MSH2 gene, in genomic DNA isolated from human peripheral whole blood specimens. P003 MLH1/MSH2 is intended to confirm a potential cause for and clinical diagnosis of Lynch syndrome, aid with patient management decisions and for molecular genetic testing of at-risk family members.

For the full intended purpose, see the product description.

Clinical background

Lynch syndrome (LS), sometimes also referred to as hereditary non-polyposis colorectal cancer (HNPCC, encompassing LS and all other forms of MMR-deficient and MMR-proficient hereditary nonpolyposis colorectal cancer), is a hereditary cancer susceptibility syndrome, predisposing to several cancer types (GeneReviews). It is an autosomal dominantly inherited syndrome with gene-dependent, age-related penetrance. Prevalence of LS in the general population can be estimated at 1:280 (Evans et al. 2021). LS accounts for ~3% of all colorectal cancer cases (Moreira et al. 2012; Jiang et al. 2019; Dong et al. 2020), ~3% of endometrial cancer cases (Kahn et al. 2019) and ~10-15% of hereditary ovarian cancers (Nakamura et al. 2014).

LS is caused by heterozygous germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2 (GeneReviews). Tumours exhibit MMR deficiency, which is the consequence of somatic inactivation of the second allele of the affected gene and leads to instability of microsatellite sequences in the tumour genome.

Nonsense, missense, frameshift and splicing variants, small deletions and insertions, as well as deletions or duplications of one or more exons, are responsible for loss of function of the inherited, predisposing MMR allele. Most pathogenic variants are reported in MLH1 (15-40%) and MSH2 (20-40%); germline mutations in MSH6 (12-35%) and PMS2 (5-25%) are slightly less common (GeneReviews).

Large genomic rearrangements in these MMR genes occur with varying frequencies (20-40% of pathogenic variants in MSH2, 10-20% of pathogenic variants in MLH1, 0-10% of pathogenic variants in MSH6, 20-55% of pathogenic variants in PMS2) depending on the population studied.

In addition, constitutional epimutations of MLH1 or MSH2 genes have been identified as a rare aetiology of LS. Constitutional tissue‐specific promoter methylation can be inherited as secondary epimutation, due to a deletion involving the last exons of the EPCAM gene. This leads to methylation of the adjacent MSH2 promoter, thereby silencing of this gene in EPCAM-expressing tissues, such as the colorectum. These EPCAM deletions occur in about 1–3% of LS families (Tutlewska, Lubinski, and Kurzawski 2013).

Another rare cause of LS is a 10 Mb inversion of chromosome 2p with one breakpoint in intron 7 of MSH2. First described in literature in a family with LS in 2002 (three family members found to have the inversion) (Chen 2008; Wagner et al. 2002), this rearrangement was later identified in ten cases out of a cohort of 101 patients suspected of having LS (Rhees, Arnold, and Boland 2014).

Regulatory status

SALSA MLPA Probemix P003 MLH1/MSH2 is CE-marked under the IVDR for in vitro diagnostic (IVD) use in Europe. This assay has also been registered for IVD use in Colombia and Israel.

This assay is for research use only (RUO) in all other territories.

SALSA Sample DNA for this product

SALSA Binning DNA SD052 is an artificial DNA sample with a signal for all probes in the P003 MLH1/MSH2 probemix. Inclusion of a reaction with SD052 in initial experiments and in experiments following a change in electrophoresis conditions is recommended to aid in the creation of a bin set that links peaks to the probes that produce them. Binning DNA cannot be used as a reference sample in the MLPA data analysis, and cannot be used to quantify the signals of mutation-specific probes.

A vial of SALSA Binning DNA SD052 is included with every order of the P003 MLH1/MSH2 probemix, but it is possible to order additional vials separately.

For more information, see the product description.

Product documentation

Version D1

Other versions

Contact us for earlier versions.

Translations and Summary of Safety and Performance

Translations of the product description in selected European languages are available upon request. Please contact us or one of our local sales partners. Translations of the MLPA General Protocol in selected languages are available here.

The Summary of Safety and Performance (SSP) is also available upon request.

List prices

Product

Item no.
Description
Technology
Price
P003-025R
SALSA MLPA Probemix P003 MLH1/MSH2 – 25 rxn
MLPA
€ 286.00
P003-050R
SALSA MLPA Probemix P003 MLH1/MSH2 – 50 rxn
MLPA
€ 560.00
P003-100R
SALSA MLPA Probemix P003 MLH1/MSH2 – 100 rxn
MLPA
€ 1096.00

Required reagents

A general SALSA MLPA Reagent Kit is required for MLPA experiments (to be ordered separately).

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA Reagent Kit – 100 rxn – FAM (6 vials)
MLPA MS-MLPA
€ 348.00
EK1-CY5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 348.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK5-CY5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6152.00

Sample DNAs (included)

A vial is included with every order of this probemix, but additional vials can also be purchased separately.

Item no.
Description
Technology
Price
SD052
SALSA Binning DNA SD052 – 6 rxn
MLPA
€ 24.15

Price details & ordering

The prices above are list prices for direct orders from MRC Holland. Contact us for a quote that takes discounts and additional costs (such as shipping costs) into account. Different prices apply for orders through one of our sales partners; contact your local supplier for a quote.

More information about ordering & prices

Positive samples

Inclusion of a positive sample is usually not required, but can be useful for the analysis of your experiments. MRC Holland has very limited access to positive samples and cannot supply such samples. We recommend using positive samples from your own collection. Alternatively, you can use positive samples from an online biorepository, such as the Coriell Institute.

We have no information about specific commercially available positive samples that can be used with this product.

Comparison of Lynch syndrome and polyposis syndrome products

MRC Holland offers various different assays for Lynch syndrome and polyposis syndrome. The table below indicates which product can be used for which target gene(s).

Currently Viewing Currently Viewing Currently Viewing Currently Viewing Currently Viewing Currently Viewing Currently Viewing Currently Viewing
D001/D002 P003 P248 P008 P072 ME011 P043 P378
Properties CE-marked no yes yes yes yes yes yes yes
Technique digitalMLPA MLPA MLPA MLPA MLPA MS-MLPA MLPA MLPA
Lynch syndrome (HNPCC) MLH1 ✓ ✓ ✓ ✓
MSH2 ✓ ✓ ✓ ✓ ✓
MSH6 ✓ ✓ ✓
PMS2 ✓ ✓ ✓
EPCAM ✓ ✓ ✓ ✓
Polyposis syndrome FAP/AFAP: APC ✓ ✓
MAP: MUTYH ✓ ✓ ✓ ✓
Product page D001/D002 P003 P248 P008 P072 ME011 P043 P378

Resources

General MLPA resources

MLPA education

Publications

Selected publications using P003 MLH1/MSH2

  • Carneiro da Silva F et al. (2015). Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome. PLoS One. 10:e0139753.
  • Ikenoue T et al. (2019). Importance of gastric cancer for the diagnosis and surveillance of Japanese Lynch syndrome patients. J Hum Genet. 64:1187-94.
  • Keränen A et al. (2018). Testing strategies to reduce morbidity and mortality from Lynch syndrome. Scand J Gastroenterol. 53:1535-40.
  • Lepkes L et al. (2021). Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer. Cancers (Basel). 13:118.
  • Loizidou MA et al. (2014). The mutational spectrum of Lynch syndrome in Cyprus. PLoS One. 9:e105501.
  • Rossi BM et al. (2017). A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 17:623.
  • Rubio I et al. (2016). Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer. Oncology. 91:171-6.
  • Smith MJ et al. (2016). The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. Hum Mutat. 37:250-6.
  • Tian W et al. (2019). Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. Int J Cancer. 145:1290-8.
  • Tsaousis GN et al. (2019). Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 19:535.

References

  • Chen JM (2008). The 10-Mb paracentric inversion of chromosome arm 2p in activating MSH2 and causing hereditary nonpolyposis colorectal cancer: re-annotation and mutational mechanisms. Genes Chromosomes Cancer. 47:543-5.
  • Dong L et al. (2020). Distinct clinical phenotype and genetic testing strategy for Lynch syndrome in China based on a large colorectal cancer cohort. Int J Cancer. 146:3077-86.
  • Evans DG et al. (2022). Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers. J Med Genet. 59:328-34.
  • Jiang W et al. (2019). Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. Int J Cancer. 144:2161-8.
  • Kahn RM et al. (2019). Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer. 125:3172-83.
  • Moreira L et al. (2012). Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 308:1555-65.
  • Nakamura K et al. (2014). Features of ovarian cancer in Lynch syndrome (Review). Mol Clin Oncol. 2:909-16.
  • Rhees J et al. (2014). Inversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population. Fam Cancer. 13:219-25.
  • Tutlewska K et al. (2013). Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review. Hered Cancer Clin Pract. 11:9.
  • Wagner A et al. (2002). A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. Genes Chromosomes Cancer. 35:49-57.
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Choose your country to see the products for your location

CE

CE-marked products are for In Vitro Diagnostic (IVD) use only in EU (candidate) member states and members of the European Free Trade Association (EFTA), and the UK.

CE2797

CE-marked products are for In Vitro Diagnostic (IVD) use only in EU (candidate) member states and members of the European Free Trade Association (EFTA), and the UK.

CO

IVD-registered in Colombia.

IL

IVD-registered in Israel.