rs146359682
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000179.3(MSH6):āc.2950A>Cā(p.Asn984His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000887 in 1,577,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N984D) 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.2950A>C | p.Asn984His | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2950A>C | p.Asn984His | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000223 AC: 5AN: 223886Hom.: 0 AF XY: 0.0000166 AC XY: 2AN XY: 120542
GnomAD4 exome AF: 0.00000631 AC: 9AN: 1425646Hom.: 0 Cov.: 34 AF XY: 0.00000425 AC XY: 3AN XY: 705866
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MSH6: PM2, BP1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 18, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2022 | 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 published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23621914, 17531815, 21120944) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 11, 2019 | The MSH6 c.2950A>C; p.Asn984His variant (rs146359682) is reported in ClinVar (Variation ID: 186492). This variant is found in the general population with an overall allele frequency of 0.002% (5/223886 alleles) in the Genome Aggregation Database. The asparagine at codon 984 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, a different bioinformatics tool (CoDP) developed specifically to predict the impact of missense variants on MSH6, suggests that this variant does not impact MSH6 protein (Terui 2013). However, given the lack of clinical and functional data, the significance of the p.Asn984His variant is uncertain at this time. REFERENCES Terui H et al. CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. J Biomed Sci. 2013 Apr 28;20:25. - |
Lynch syndrome 5 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 28, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 25, 2017 | - - |
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 28, 2023 | This missense variant replaces asparagine with histidine at codon 984 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 an individual affected with pancreatic cancer (PMID: 29684080). This variant has been identified in 5/223886 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 | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 29, 2015 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2024 | The p.N984H variant (also known as c.2950A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2950. The asparagine at codon 984 is replaced by histidine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with uterine cancer at 70 who had a family history of colorectal cancer (Walker R et al. Cancers (Basel), 2023 Oct;15:). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2022 | This missense variant replaces asparagine with histidine at codon 984 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 an individual affected with thyroid cancer (PMID: 29684080). This variant has been identified in 5/223886 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2021 | Variant summary: MSH6 c.2950A>C (p.Asn984His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 223886 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.2950A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at