rs184131049
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_000179.3(MSH6):c.3992G>A(p.Arg1331Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,609,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. R1331L) 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.3992G>A | p.Arg1331Gln | missense_variant | 9/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3992G>A | p.Arg1331Gln | missense_variant | 9/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151626Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245650Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133152
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1457508Hom.: 0 Cov.: 35 AF XY: 0.00000414 AC XY: 3AN XY: 725240
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151626Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73998
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 27294619, 22851212, 26991699, 17531815, 21120944, 12019211, 31857677) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 12, 2023 | In the published literature, this variant as a somatic variant in a colorectal cancer tumor, with microsatellite instability and discordant immunohistochemical results (PMID: 31857677 (2020)). In the same study, the variant was found to co-occur with a germline pathogenic MSH6 variant (PMID: 31857677 (2020)). The frequency of this variant in the general population, 0.0000041 (1/245650 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 18, 2023 | This missense variant replaces arginine with glutamine at codon 1331 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/245650 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. - |
Lynch syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: MSH6 c.3992G>A (p.Arg1331Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245650 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3992G>A has been reported in the germline of individuals affected with Prostate Cancer or Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and two classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 27, 2023 | This missense variant replaces arginine with glutamine at codon 1331 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with gastric cancer (Universal Mutation Database, PMID: 10612827. This variant has been identified in 1/245650 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. - |
MSH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 02, 2024 | The MSH6 c.3992G>A variant is predicted to result in the amino acid substitution p.Arg1331Gln. To our knowledge, this variant has not been reported in the literature as a germline variant. This variant is reported in 0.0063% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/419915/?new_evidence=true). Another missense variant affecting this residue has been associated with colorectal cancer (p.Arg1331Pro; Belvederesi et al. 2012. PubMed ID: 22851212). At this time, the clinical significance of the c.3992G>A variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at