3-37028863-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000249.4(MLH1):c.1489C>T(p.Arg497Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251486Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727228
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74470
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 9/282892 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. -
The p.R497W variant (also known as c.1489C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1489. The arginine at codon 497 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).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 variant remains unclear. -
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not provided Uncertain:2
This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg497Trp was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg497Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PMS2/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg497Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121412 (1/40469), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
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Lynch syndrome Uncertain:1
This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Other:1
Variant interpreted as Uncertain significance and reported on 10-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at