rs63750792
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.83C>T(p.Pro28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.52
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a helix (size 13) in uniprot entity MLH1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_000249.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 3-36993630-C-T is Pathogenic according to our data. Variant chr3-36993630-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90388.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993630-C-T is described in Lovd as [Pathogenic]. Variant chr3-36993630-C-T is described in Lovd as [Benign]. Variant chr3-36993630-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 exome
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1
AN:
1461874
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Cov.:
31
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1
AN XY:
727238
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2016 | Variant summary: The MLH1 c.83C>T (p.Pro28Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121156 control chromosomes. This variant has been reported in multiple affected individuals and functional studies showed that variant causes deficient MMR activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability >0.99 - |
| Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | Jan 30, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 29, 2022 | This missense variant replaces proline with leucine at codon 28 in the ATPase domain 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). Functional studies have shown that this variant has deficient MMR activity (PMID: 16083711, 17510385) and decreases protein stability and ability to bind EXO1 and/or PMS2 (PMID: 12810663, 17594722, 21404117). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12362047, 16083711, 16736289, 21404117, 23741719), suspected Lynch syndrome (PMID: 21642682, 28874130), or colorectal cancer (PMID: 10323887, 23741719). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2022 | The p.P28L pathogenic mutation (also known as c.83C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 83. The proline at codon 28 is replaced by leucine, an amino acid with similar properties. This mutation has been found in multiple families that meet Amsterdam I or Amsterdam II criteria for Lynch syndrome, or had a personal and family history of an HNPCC-related cancer (Kurzawski G et al. J Med Genet. 2002 Oct;39(10):E65; Raevaara, T et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, individuals with this mutation have concordant tumor studies showing microsatellite instability and/or loss of MLH1 with immunohistochemistry (Raevaara T et al. Gastroenterology. 2005 Aug;129(2):537-49; Spaepen et al. Familial Cancer, 2006 ;5(2):179-89; Mangold et al. J Pathol 2005 Dec;207(4):385-95; Lamberti C et al. Gut 1999 Jun;44(6):839-43). Multiple functional studies have reported that this mutation causes reduced mismatch repair efficiency compared to the wild-type allele (Raevaara T et al. Gastroenterology. 2005 Aug;129(2):537-49; Takahashi M et al. Cancer Res. 2007 May 15;67(10):4595-604). This mutation is in the ATPase domain of MLH1 and other functional studies have reported that it disrupts the interaction of the MLH1 protein with PMS2, supporting that it is pathogenic (Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84; Kondo E et al. Cancer Res. 2003 Jun 15;63(12):3302-8). This alteration has been classified as a class 5 mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 09, 2020 | The variant has been reported in families affected with colorectal cancer in the published literature (PMID: 9298827 (1997), 12362047 (2002), 16451135 (2006), 16736289 (2006), 21404117 (2011), 28874130 (2017)). Additionally, functional studies have observed the variant with reduced mismatch repair activity, expression, and stability (PMID: 21404117 (2011), 17510385 (2007), 16083711 (2005)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Therefore, the variant is classified as pathogenic. - |
MLH1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 04, 2024 | The MLH1 c.83C>T variant is predicted to result in the amino acid substitution p.Pro28Leu. This variant has been reported in individuals with Lynch syndrome (Kurzawski et al. 2002. PubMed ID: 12362047; Raevaara et al. 2005. PubMed ID: 16083711; Spaepen et al. 2006. PubMed ID: 16736289; Hardt et al. 2011. PubMed ID: 21404117), suspected Lynch syndrome (Rossi et al. 2017. PubMed ID: 28874130), and colorectal cancer (Thompson et al. 2012. PubMed ID: 22949387). Functional studies have shown that this variant decreases mismatch repair activity (Raevaara et al. 2005. PubMed ID: 16083711; Takahashi et al. 2007. PubMed ID: 17510385) and protein stability and ability to bind EXO1 and/or PMS2 (Kondo et al. 2003. PubMed ID: 12810663; Ou et al. 2007. PubMed ID: 17594722; Hardt et al. 2011. PubMed ID: 21404117). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 26, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the MLH1 protein (p.Pro28Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 16083711, 16736289). ClinVar contains an entry for this variant (Variation ID: 90388). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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: 10082584, 17210669, 17510385). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of helix (P = 0.0854);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at