rs786201776
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000179.3(MSH6):c.166_171dup(p.Gly56_Pro57dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,568,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P55P) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.166_171dup | p.Gly56_Pro57dup | inframe_insertion | 1/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.166_171dup | p.Gly56_Pro57dup | inframe_insertion | 1/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000589 AC: 1AN: 169852Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 94178
GnomAD4 exome AF: 0.00000212 AC: 3AN: 1416660Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1AN XY: 701508
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2016 | This duplication of six nucleotides is denoted MSH6 c.166_171dupGGGCCC at the cDNA level and p.Gly56_Pro57dup (G56_P57dup) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GCCT[GGGCCC]AGGC. This in-frame duplication occurs in a region which is not conserved and is not located in a known functional domain (Terui 2013, Kariola 2002). This variant has not, to our knowledge, been published in the literature as either pathogenic or benign. Since in frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Gly56_Pro57dup to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 16, 2022 | PM2, PM4 - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 24, 2021 | This variant causes an in-frame duplication of two amino acids of the MSH6 protein. 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 2/201112 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | The c.166_171dupGGGCCC variant (also known as p.G56_P57dup), located in coding exon 1 of the MSH6 gene, results from an in-frame duplication of GGGCCC at nucleotide positions 166 to 171. This results in the duplication of 2 extra residues (GP) between codons 56 and 57. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
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 variant causes an in-frame duplication of two amino acids of the MSH6 protein. 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 2/201112 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. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This variant, c.166_171dup, results in the insertion of 2 amino acid(s) of the MSH6 protein (p.Gly56_Pro57dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786201776, gnomAD 0.004%). 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: 184901). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at