rs121912961
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The ENST00000458205.6(MLH1):c.-374C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000821 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
ENST00000458205.6 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
- Lynch syndrome 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251388 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461766Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727186 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:11
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The MLH1 c.350C>T (p.Thr117Met) variant has been reported in the published literature in individuals affected with Lynch syndrome-associated cancer (PMIDs: 16451135 (2006), 28135145 (2017), 28449805 (2017), 28874130 (2017), 30521064 (2019)). Functional studies indicate this variant causes significantly reduced MLH1 protein expression and DNA mismatch repair activity (PMIDs: 11781295 (2002), 17135187 (2006), 17510385 (2007), 23403630 (2013)). The frequency of this variant in the general population, 0.000004 (1/251388 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
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Published functional studies demonstrate a damaging effect: abrogated or significantly reduced MMR activity, no dominant mutator effect (Shimodaira 1998, Shcherbakova 1999, Trojan 2002, Plotz 2006, Vogelsang 2009, Hinrichsen 2013, Thompson 2014); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22736432, 11429708, 23403630, 12377806, 22949379, 25420488, 25980754, 28874130, 10082584, 18547406, 23760103, 22949387, 25117503, 15340264, 19267393, 12200596, 12112654, 14564042, 12373605, 12919140, 11601928, 16395668, 19072991, 15996210, 18726168, 18772310, 21387278, 12555990, 18618713., 21642682, 16995940, 18561205, 17192056, 18383312, 11385712, 11139242, 16451135, 12362047, 16528606, 18566915, 17713103, 15713769, 20215533, 24362816, 9697702, 11781295, 12810663, 17135187, 17510385, 17594722, 19863800, 20864636, 20176959, 20020535, 22753075, 8574961, 27064304, 27601186, 27013479, 22322191, 28127413, 28449805, 28251689, 26681312, 28640387, 25248401, 29478780, 29752822, 28135145, 29505604, 8566964, 10732761, 16830052, 17026620, 9806477, 30521064, 29887214, 30720243, 30998989, 31054147, 31350202, 31491536, 31447099, 31948886, 32719484, 31332305, 33654310) -
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Lynch syndrome Pathogenic:5
The p.Thr117Met variant in MLH1 has been reported in >50 individuals with MLH1-a ssociated tumors (Kurzawski 2002, Wei 2003, Liu 1996, Maliaka 1996, Yap 2008, Ca sey 2005; InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants. php) and segregated with disease in at least 2 affected family members (Zavodna 2006). This variant was absent from large population studies. In vitro functiona l studies provide some evidence that the p.Thr117Met variant is deficient in mis match repair (Trojan 2002). Computational prediction tools and conservation anal ysis suggest that this variant may impact the protein, though this information a lone is not predictive enough to determine pathogenicity. Additionally, this var iant has been classified as pathogenic on Nov 26, 2014 by the ClinGen-approved I nSiGHT panel (ClinVar SCV000211908.2). In summary, this variant meets our criter ia to be classified as pathogenic for Lynch syndrome in an autosomal dominant ma nner. ACMG/AMP criteria applied: PS4, PM2, PS3, PP3 (Richards 2015). -
Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99 -
Variant summary: The c.350C>T variant in MLH1 gene is a missense change that alters a highly conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant has been reported in multiple affected individuals and was shown to segregate with the disease (Wei_CG_2003). IHC showed selective loss of the MLH1 protein in tumors from patients testing positive for the variant of interest and cells containing the T117M lost the ability to repair mismatched DNA both in vivo and in vitro (Takanashi, 2007; Hinrichsen, 2016). The variant is absent from the large control population dataset of ExAC. Lastly, a reputable database/diagnostic center classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -
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This missense variant replaces threonine with methionine at codon 117 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have reported that this variant impacted in vitro mismatch repair activity (PMID: 11781295, 17135187, 17510385, 20020535, 23403630). This variant has been reported in over 20 individuals and families affected with Lynch syndrome (PMID: 8566964, 8574961, 9806477, 10349986, 10480359, 10732761, 11385712, 12362047, 12200596, 12373605, 12919140, 20233461, 15713769, 17026620, 18566915, 19419416, 19698169, 21404117, 22322191, 23403630) and has been reported to segregate with disease in multiple families (PMID: 22949379). This variant has been identified in 1/251388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
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This sequence change replaces threonine with methionine at codon 117 of the MLH1 protein (p.Thr117Met). This variant is not present in population databases (gnomAD). This variant has been observed in many families and individuals with colon cancer and Lynch syndrome (PMID: 18566915, 22322191, 20233461, 15713769, 12112654, 19698169). ClinVar contains an entry for this variant (Variation ID: 17094). Multiple experimental studies have shown that this missense change results in an unstable protein with disrupted protein interactions and defective mismatch repair activity (PMID: 11781295, 17135187, 23403630, 12810663, 11429708, 17510385, 9697702). A multifactorial likelihood analysis incorporating genetic, clinical, and bioinformatic data (PMID: 19267393), and an algorithm developed specifically for the MLH1 gene (PMID: 18383312), indicate that this variant has a high probability of being pathogenic. In addition, multiple missense mutations have been reported in this region in individuals with colorectal cancer, suggesting that this is an important domain for MLH1 function (PMID: 17510385). In-silico predictions show pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 1 benign prediction from PrimateAI and the threonine residue is highly conserved. Therefore, this sequence change has been classified as Pathogenic. -
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Lynch syndrome 1 Pathogenic:2
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Hereditary cancer-predisposing syndrome Pathogenic:2
This missense variant replaces threonine with methionine at codon 117 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have reported that this variant impacted in vitro mismatch repair activity (PMID: 11781295, 17135187, 17510385, 20020535, 23403630). This variant has been reported in over 20 individuals and families affected with Lynch syndrome (PMID: 8566964, 8574961, 9806477, 10349986, 10480359, 10732761, 11385712, 12362047, 12200596, 12373605, 12919140, 20233461, 15713769, 17026620, 18566915, 19419416, 19698169, 21404117, 22322191, 23403630) and has been reported to segregate with disease in multiple families (PMID: 22949379). This variant has been identified in 1/251388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
The c.350C>T (p.T117M) alteration is located in coding exon 4 of the MLH1 gene. This alteration results from a C to T substitution at nucleotide position 350, causing the threonine (T) at amino acid position 117 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/251388) total alleles studied. The highest observed frequency was 0.003% (1/34592) of Latino alleles. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients meeting Amsterdam diagnostic criteria; several whose tumors demonstrated high microsatellite instability and/or loss of MLH1 staining by immunohistochemistry (IHC) (Buerstedde, 1995; Maliaka, 1996; Bennett, 1998; Kurzawski, 2002; Wei, 2003; Pigatto, 2004; Christensen, 2008; Ollila, 2008; Nilbert, 2009; Choi, 2009; Yap, 2009; Vogelsang, 2009; Walsh, 2012; Toon, 2013; Rosty, 2014; Shirts, 2016; Susswein, 2016; Sunga, 2017; Jiang, 2019; Tian, 2019; Ow, 2019; Yanus, 2020; Talbot, 2021; Frostberg, 2021). This mutation has also been reported in breast and prostate cancer cohorts (Walsh, 2010; Rosty, 2014; Li, 2019; Wu, 2020). Two other alterations at the same codon, p.T117R and p.T117K, have been detected in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients meeting Amsterdam diagnostic criteria (Buerstedde, 1995; Heinimann, 1999; Ellison, 2001; Casey, 2005; Stojcev, 2013), and based on an internal structural assessment, both of these variants are anticipated to result in a significant decrease in structural stability (Ambry internal data). This amino acid position is well conserved in available vertebrate species. Multiple functional studies have demonstrated that the T117M alteration has reduced protein expression, deficient MMR activity, inactivated hMLH1-induced dominant mutator effect, and impaired interaction with hPMS2 (Shimodaira, 1998; Jäger, 2001; Trojan, 2002; Brieger, 2002; Takahashi, 2007; Drost, 2010; Hinrichsen, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Endometrial carcinoma Pathogenic:2
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The MLH1 p.Thr117Met variant was identified in the literature in at least 2 of 160 proband chromosomes from Lynch syndrome families, and has been characterized in several functional studies (Andersen 2012, Brieger 2002, Hinrichsen 2013, Jager 2001, Liu 1996, Perera 2010, Plotz 2006, Takahashi 2007, Trojan 2002, Vogelsang 2009), and was previously identified by our laboratory in 1 individual with colorectal cancer. The p.Thr117Met variant was also identified in dbSNP (ID: rs63750781) “With allele of Uncertain significance”, MutDB, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, “MMR Gene Unclassified Variants Database”, UMD (28X as a Causal variant), LOVD and was classified as pathogenic by InSiGHT and OMIM (submitted within the ClinVar database). The p.Thr117Met residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Thr117Met variant may impact the protein. A study by Perera (2010) found that the p.Thr117Met variant was associated with significantly unbalanced allelic expression, and tumour analysis of the positive proband showed MLH1-deficiency and high microsatellite instability, suggesting that this could be considered a deleterious mutation. Functional studies characterizing the variant demonstrated reduced mismatch repair activity and nuclear localization (Andersen_2012, Brieger 2002, Jager 2001, Trojan 2002, Takahashi 2007, Plotz 2006, Vogelsang 2009); some of these studies detected normal expression of MLH1 and interaction with PMS2, while other studies found a reduction in MLH1 expression and PMS2 interaction. Three studies have suggested that the p.Thr117Met missense mutation may inactivate mismatch repair (MMR) activity by altering the capacity of this mutant protein to bind and/or hydrolyze adenosine triphosphate (ATP) (Brieger 2002, Jager 2001, Drost 2009). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Inherited MMR deficiency (Lynch syndrome) Pathogenic:1
PS4_Very Strong,PM2,PP3,PP4_Very Strong -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
PM2_Supporting+PP3+PS4+PS3_VeryStrong -
Lynch-like syndrome Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 117 of the MLH1 protein (p.Thr117Met). This variant is present in population databases (rs63750781, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer and Lynch syndrome (PMID: 12112654, 15713769, 18566915, 19698169, 20233461, 22322191). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 17094). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11429708, 11781295, 12810663, 17135187, 17510385, 23403630). This variant disrupts the p.Thr117 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9697702, 11555625, 12810663). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Colon cancer Pathogenic:1
is neutral and non-polar, at codon 117 of the MLH1 protein (p.Thrl 17Met). This variant is present in population databases (rs63750781, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer and Lynch syndrome (PMID: 12112654, 15713769, 18566915, 19698169, 20233461, 22322191). ClinVar contains an entry for this variant (Variation ID: 17094). Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11429708, 1178i295, 12810663, 17135187, 17510385, 23403630). This variant disrupts the p.Thrl 17 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9697702, 11555625, 12810663). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic variants in the MLH1 gene are known to cause Hereditary Non-Polyposis Colorectal Cancer Syndrome, also known as Lynch Syndrome. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at