chr2-47801045-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000179.3(MSH6):āc.3062C>Gā(p.Ala1021Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,595,222 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. A1021L) has been classified 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3062C>G | p.Ala1021Gly | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3062C>G | p.Ala1021Gly | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000843 AC: 2AN: 237366Hom.: 0 AF XY: 0.0000156 AC XY: 2AN XY: 128112
GnomAD4 exome AF: 0.0000111 AC: 16AN: 1443092Hom.: 0 Cov.: 34 AF XY: 0.00000838 AC XY: 6AN XY: 716152
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2024 | The p.A1021G variant (also known as c.3062C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 3062. The alanine at codon 1021 is replaced by glycine, an amino acid with similar properties. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 22, 2019 | This missense variant replaces alanine with glycine at codon 1021 of the MSH6 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/268774 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 05, 2017 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces alanine with glycine at codon 1021 of the MSH6 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/268774 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2015 | This variant is denoted MSH6 c.3062C>G at the cDNA level, p.Ala1021Gly (A1021G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has been identified in tumor tissue from an individual with brain cancer (Nguyen 2014). MSH6 Ala1021Gly 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 Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala1021Gly occurs at a position that is conserved in mammals and is located in domain III of the MutS domain (Terui 2013). 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 Ala1021Gly 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 | Oct 08, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1021 of the MSH6 protein (p.Ala1021Gly). This variant is present in population databases (rs63750287, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 418722). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at