chr3-37042296-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000249.4(MLH1):āc.1696T>Cā(p.Tyr566His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y566C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1696T>C | p.Tyr566His | missense_variant | 15/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1696T>C | p.Tyr566His | missense_variant | 15/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251156Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135752
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458744Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 725954
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2014 | This variant is denoted MLH1 c.1696T>C at the cDNA level, p.Tyr566His (Y566H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Tyr566His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Tyr566His occurs at a position that is moderately conserved across species and is located in the region of interaction with EXO1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Tyr566His is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 566 of the MLH1 protein (p.Tyr566His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182527). 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 with a negative predictive value of 95%. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2022 | The p.Y566H variant (also known as c.1696T>C), located in coding exon 15 of the MLH1 gene, results from a T to C substitution at nucleotide position 1696. The tyrosine at codon 566 is replaced by histidine, an amino acid with similar properties. This variant was identified in 1/113 Italian non-BRCA1/2 patients with a personal and/or familial history of breast cancer, ovarian cancer, and/or pancreatic cancer (Germani A et al. J Clin Med, 2020 Sep;9:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at