rs63750610
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.1943C>G(p.Pro648Arg) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P648L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 5.88
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 18 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000249.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-37048563-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89953.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.944
PP5
?
Variant 3-37048563-C-G is Pathogenic according to our data. Variant chr3-37048563-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 479696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1943C>G | p.Pro648Arg | missense_variant | 17/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1943C>G | p.Pro648Arg | missense_variant | 17/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | ClinVar contains an entry for this variant (Variation ID: 479696). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 648 of the MLH1 protein (p.Pro648Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro648 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16083711, 16724012, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2021 | The p.P648R variant (also known as c.1943C>G), located in coding exon 17 of the MLH1 gene, results from a C to G substitution at nucleotide position 1943. The proline at codon 648 is replaced by arginine, an amino acid with dissimilar properties. There are two well characterized pathogenic mutations at this same amino acid position: MLH1 p.P648S and MLH1 p.P648L (Ambry internal data). Based on internal structural assessment, this alteration will cause significant structural destabilization at a site where other destabilizing pathogenic alterations are present (Ambry internal data).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at P648 (P = 0.0228);.;.;.;.;.;
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