rs63750437
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001167617.3(MLH1):c.-60G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
MLH1
NM_001167617.3 5_prime_UTR_premature_start_codon_gain
NM_001167617.3 5_prime_UTR_premature_start_codon_gain
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.42
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 3-37000977-G-A is Pathogenic according to our data. Variant chr3-37000977-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90112.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000977-G-A is described in Lovd as [Pathogenic]. Variant chr3-37000977-G-A is described in Lovd as [Benign]. Variant chr3-37000977-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.230G>A | p.Cys77Tyr | missense_variant | 3/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.230G>A | p.Cys77Tyr | missense_variant | 3/19 | 1 | NM_000249.4 | ENSP00000231790.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 10, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 12, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Jun 29, 2022 | ACMG criteria used to clasify this variant: PM2, PM5, PS3, PM1, PS4 - |
Lynch syndrome Pathogenic:3
| 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 | Department of Pathology and Laboratory Medicine, Sinai Health System | May 06, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This missense variant replaces cysteine with tyrosine at codon 77 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 reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2023 | The p.C77Y pathogenic mutation (also known as c.230G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 230. The cysteine at codon 77 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been identified in numerous individuals meeting Amsterdam criteria for Lynch syndrome with concordant tumor microsatellite and immunohistochemistry results (Hardt Ket al. Fam. Cancer. 2011 Jun; 10(2):273-84; Fokkema IF et al. Hum. Mutat. 2011 May; 32(5):557-63). Functional studies of the p.C77Y alteration have demonstrated impaired/reduced MLH1 expression, sub-cellular localization, and mismatch repair activity compared to wild-type MLH1 protein (Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604; Kondo E et al. Cancer Res. 2003 Jun; 63(12):3302-8; Wanat JJ et al. Hum. Mol. Genet. 2007 Feb;16(4):445-52; Shimodaira H et al. Nat. Genet. 1998 Aug; 19(4):384-9; Plotz G et al. Nucleic Acids Res. 2006;34(22):6574-86). Functional studies of another amino acid change at the same codon, p.C77R, have also shown impaired activity compared to wild-type (Nystrom-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33(2):160-7; Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, the p.C77Y alteration has been classified as definitely pathogenic 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | Feb 01, 2023 | This missense variant replaces cysteine with tyrosine at codon 77 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 reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). 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 | Jan 30, 2023 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with Lynch syndrome (PMIDs: 28135145 (2017), 21404117 (2011), 19669161 (2010), 15849733 (2005), 9032648 (1997)), and is classified as pathogenic in a multifactorial analysis study (PMID: 22949379 (2013)). Functional studies also indicate this variant has deleterious effects on MLH1 protein expression and DNA mismatch repair activity (PMIDs: 17510385 (2007), 17210669 (2007), 17135187 (2006), 12810663 (2003), 9697702 (1998)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 77 of the MLH1 protein (p.Cys77Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary non-polyposis colorectal cancer (PMID: 9032648, 15849733, 17510385, 21404117). ClinVar contains an entry for this variant (Variation ID: 90112). 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: 12810663, 17135187, 17210669, 17510385, 18383312, 22949379, 22949387). This variant disrupts the p.Cys77 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11793442, 16083711, 18383312, 24362816). 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. - |
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
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at C77 (P = 0.0827);
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