rs575714670
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6
The NM_000179.3(MSH6):c.3886A>C(p.Lys1296Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1296E) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3886A>C | p.Lys1296Gln | missense_variant | 9/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3886A>C | p.Lys1296Gln | missense_variant | 9/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250668Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135590
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461728Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727170
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74458
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2016 | The p.K1296Q variant (also known as c.3886A>C), located in coding exon 9 of the MSH6 gene, results from an A to C substitution at nucleotide position 3886. The lysine at codon 1296 is replaced by glutamine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.398 (Terui H et al. J. Biomed. Sci. 2013;20:25). 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 | Oct 31, 2023 | This missense variant replaces lysine with glutamine at codon 1296 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 been identified in 2/250668 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at