3-37048979-C-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000249.4(MLH1):c.2065C>A(p.Gln689Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q689R) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 4.42
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 4 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 chr3-37048980-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.2065C>A | p.Gln689Lys | missense_variant | 18/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.2065C>A | p.Gln689Lys | missense_variant | 18/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251164Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135730
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727204
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 30, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | 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 not expected to disrupt MLH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 232338). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs41542214, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 689 of the MLH1 protein (p.Gln689Lys). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2024 | The p.Q689K variant (also known as c.2065C>A), located in coding exon 18 of the MLH1 gene, results from a C to A substitution at nucleotide position 2065. The glutamine at codon 689 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;.;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
B;.;.;.;.;.
Vest4
MutPred
Gain of methylation at Q689 (P = 0.0019);.;.;.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at