rs542838372
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000179.3(MSH6):c.1729C>A(p.Arg577Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R577C) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1729C>A | p.Arg577Ser | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1729C>A | p.Arg577Ser | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | 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 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. ClinVar contains an entry for this variant (Variation ID: 479960). This missense change has been observed in individual(s) with clinical features of MSH6-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 577 of the MSH6 protein (p.Arg577Ser). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2021 | The p.R577S variant (also known as c.1729C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1729. The arginine at codon 577 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly 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