rs63750792
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.83C>T | p.Pro28Leu | missense_variant | 1/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.83C>T | p.Pro28Leu | missense_variant | 1/19 | 1 | NM_000249.4 | P1 |
Frequencies
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 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | Jan 30, 2019 | - - |
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 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
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. - |
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. - |
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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 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 of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at