rs754554026
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000249.4(MLH1):c.1490G>A(p.Arg497Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 2.71
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_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.24122486).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1490G>A | p.Arg497Gln | missense_variant | 13/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1490G>A | p.Arg497Gln | missense_variant | 13/19 | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251480Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727242
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | The p.R497Q variant (also known as c.1490G>A), located in coding exon 13 of the MLH1 gene, results from a G to A substitution at nucleotide position 1490. The arginine at codon 497 is replaced by glutamine, an amino acid with highly similar properties. This alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2022 | This missense variant replaces arginine with glutamine at codon 497 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 7/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2023 | Variant summary: MLH1 c.1490G>A (p.Arg497Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1490G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 16, 2023 | This missense variant replaces arginine with glutamine at codon 497 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual suspected of having hereditary breast/ovarian cancer (PMID: 34359559). This variant has been identified in 7/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 29596542, 22608206) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;.;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;.;.;.;.
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;D;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;D;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;.;.;.;.;.;.;.
Vest4
MutPred
Loss of helix (P = 0.0093);.;.;.;.;.;.;.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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