MLH1

Gene Facts

• HGNC Symbol: MLH1 (HGNC:7127)
• HGNC Name: mutL homolog 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: COCA2
• Alias symbols: HNPCC, FCC2, HNPCC2, MLH-1
• %HI: 3.18
• pLI: 0
• LOEUF: 0.64
• Cytoband: 3p22.2
• Genomic Coordinates:

  GRCh37/hg19:	chr3:37035009-37092337
  GRCh38/hg38:	chr3:36993466-37050846

• MANE Select Transcript: NM_000249.4 ENST00000231790.8
• Function: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points f... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-1421
• ClinGen Curation ID: CCID:007469
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/13/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Lynch syndrome 2

HI Evidence

• PUBMED: 14635101
  Taylor et al (2003) screen 215 subjects referred to a clinic for phenotype consistent with autosomal dominant familial nonpolyposis colon cancer (Lynch Syndrome) and identify 6 MLH1 deletions (as well as 10 novel MLH1 mutations.)
• PUBMED: 15942939
  van der Klift (2005) screened a large cohort of families with hereditary nonpolyposis colon cancer and identified 13 MLH1 deletions from 68 unrelated kindreds.
• PUBMED: 16955466
  Plasilova, et al. (2006) presented a 31-year-old male (patient ID: 2247/1) with colorectal cancer as well as his healthy parents and siblings. Cycle sequencing of MLH1 revealed heterozygous de novo c.666dup (p.Ser225*) variant in affected male (maternity and paternity confirmed; parents were of 57 and 52 years of age, respectively). This variant was also absent from 2 healthy sisters (age of 27 and 23, respectively) and gnomAD as of August 2021. A study on the patient’s tumor tissue showed the absence of MLH1and PMS2 expression (according to the immunohistochemical analysis), microsatellite instability-high status as well as the presence of a variant in a nearly homozygous state.
• PUBMED: 33335961
  Ghaedi, et al. (2019) presented an Iranian family with Lynch syndrome-related cancers. Whole exome sequencing in the 45-year-old male proband with colorectal cancer (age of onset 40 years; fulfilling Amsterdam clinical criteria) revealed heterozygous MLH1 c.206delG (p.R69fs) variant. Sanger sequencing in additional 16 affected family members (8 males and 8 females; the age of onset between 30 and 55 years) showed the presence of the same variant. This variant was absent from healthy family members (3 females and 1 male; between 41 and 49 years of age) and gnomAD as of August 2021. Proband’s tissue analysis showed the absence of MLH1 expression (through immunohistochemistry).
• PUBMED: 30289396
  Moufid, et al. (2018) presented a Moroccan family with Lynch syndrome. Screening of MLH1 and MSH2 revealed heterozygous MLH1 c.910dupG (p.Asp304Glyfs*3, also reported as p.D304fsX306) in 2 colon cancer patients: a 64-year-old female proband (diagnosed at age of 60) and her son (diagnosed at age of 31). This variant has also been reported in 2 of proband’s unaffected children (age of 40 and 36). This variant was absent from 3 healthy family members (2 daughters (age of 39 and 25, respectively) and grandson), 50 control individuals as well as from gnomAD as of August 2021. Immunohistochemistry study of proband’s tissue showed the absence of MLH1 and PMS2 expression. The proband’s deceased mother and brother were affected with colon cancer (diagnosed at age of 63 and 50, respectively), but they were not screened.
• PUBMED: 33468175
  Kumar, et al. (2021) presented 19 colorectal cancer (CRC) families from Poland. Whole-genome sequencing showed 2 MLH1 variants in 2 families, respectively. The MLH1 c.307-526_1558 + 1446dup (exon 4-13 duplication; (p.Val520Glyfs*19)) has been found in CRC affected father (diagnosed at age of 70), his CRC affected son (age of 37; diagnosed at age of 32), as well as unaffected daughter (age of 46). This variant was absent from healthy daughter (age of 43). Patients’ tumor samples showed an absence of MLH1 and PMS2 expression as well as high microsatellite instability status. Father's deceased brother and father were also affected with CRC (diagnosed at 40 and 57, respectively), but were not screened. The MLH1 c.1274del (p.Arg425Serfs*66) has been reported in the affected mother (endometrium cancer diagnosed at age of 48 and CRC diagnosed at age of 53), her CRC affected brother (diagnosed at age of 45) and her CRC affected daughter (diagnosed at age of 40). This variant was absent from 2 healthy family members (sister (age of 61) and granddaughter) and gnomAD as of August 2021. Patients’ tumor samples showed an absence of MLH1 and PMS2 expression while microsatellite instability analysis failed. The mother’s parents were CRC affected (age at diagnosis 63 and 53, respectively), but were not screened.

• HI Evidence Comments: PMID: 10096563 Edelmann, et al. (1999): The authors generated heterozygous (Mlh1 -/+) as well as homozygous (Mlh1 -/-) mice strain with Mlh1 null variant, and showed that 32% out of 22 Mlh1 +/- mice strains developed gastrointestinal (GI) and extra-GI tumors (at a mean age of 9.8 months) and 72% of 18 Mlh1 -/- mice strains developed GI and extra-GI tumors (at a mean age of 7 months). The authors also noted that tumors from Mlh1 +/- and Mlh1 -/- mice strains showed microsatellite instability-high status. - Gene Reviews (GR; http://www.ncbi.nlm.nih.gov/books/NBK1211/) attributes between 15% and 40% of Lynch Syndrome to pathogenic mutations in MLH1. Also, GR reported that the penetrance of colorectal cancers and extracolonic cancers associated with pathogenic variants in an MMR gene or EPCAM is less than 100%.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time (8-28-21) there is no evidence for triplosensitivity in this gene.