rs1553413048
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000179.3(MSH6):c.1669G>A(p.Gly557Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G557D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1669G>A | p.Gly557Ser | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1669G>A | p.Gly557Ser | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2023 | The p.G557S variant (also known as c.1669G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1669. The glycine at codon 557 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 24, 2023 | This missense variant replaces glycine with serine at codon 557 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 MSH6-related disorders in the literature. This variant has not been identified 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. - |
Lynch syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Gly557Ser variant was not identified in the literature nor previously identified by our laboratory increasing the likelihood this variant may be a rare variant of clinical significance. The p.Gly557 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Gly557Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Notably, this individual was reported as having a tumour that was MSI unstable and IHC deficient for MSH6, increasing the likelihood this variant may affect MSH6 protein product mismatch repair function. In addition, this variant occurs within the DNA mismatch repair connector domain, and could have a functional impact on the protein function, but further study would be required to assess this. In summary, the clinical significance of this variant cannot be determined with certainty at this time, therefore this variant is classified as a variant of unknown significance (VUS). - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2020 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. 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 expected to disrupt MSH6 protein function. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 433911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 557 of the MSH6 protein (p.Gly557Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at