2-47799167-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000179.3(MSH6):c.1184C>T(p.Thr395Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251120Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135740
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome Uncertain:1
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not provided Uncertain:1
This variant is denoted MSH6 c.1184C>T at the cDNA level, p.Thr395Ile (T395I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been observed in at least one individual with skin cancer (Shirts 2016). MSH6 Thr395Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr395Ile occurs at a position where amino acids with properties similar to Threonine are tolerated across species, and is located in the mismatch binding domain and nuclear localization signal domain (Warren 2007, Gassman 2011, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr395Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 395 of the MSH6 protein (p.Thr395Ile). This variant is present in population databases (rs767658494, gnomAD 0.006%). This missense change has been observed in individual(s) with skin cancer or suspected Lynch syndrome (PMID: 26845104, 31391288). ClinVar contains an entry for this variant (Variation ID: 224579). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.T395I variant (also known as c.1184C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1184. The threonine at codon 395 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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