rs267608065
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.2348_2349del(p.Cys783Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C783C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2348_2349del | p.Cys783Ter | frameshift_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2348_2349del | p.Cys783Ter | frameshift_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Endometrial carcinoma Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Cys783X variant was identified in individuals with HNPCC although no frequency data was provided (Steinke 2008, Talseth-Palmer 2010). The variant was also identified in dbSNP (ID: rs267608065) “With pathogenic allele”, the Clinvitae database as pathogenic, InSiGHT Colon Cancer Gene Variant Database as pathogenic, the ClinVar database (classified as a pathogenic variant and reviewed by an expert panel). The p.Cys783X variant leads to a premature stop codon at position 783, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 31, 2021 | - - |
Lynch syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 17, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2017 | This deletion of two nucleotides is denoted MSH6 c.2348_2349delGT at the cDNA level and p.Cys783Ter (C783X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCT[delGT]AACC. The deletion creates a nonsense variant, which changes a Cysteine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2348_2349delGT has been reported in two individuals with colorectal cancer whose tumors showed loss of MSH6 protein on immunohistochemistry (Steinke 2008, Talseth-Palmer 2010). This variant is considered pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2023 | This sequence change creates a premature translational stop signal (p.Cys783*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 18301448, 20487569). ClinVar contains an entry for this variant (Variation ID: 89274). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2021 | The c.2348_2349delGT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2348 to 2349, causing a translational frameshift with a predicted alternate stop codon (p.C783*). The alteration was initially reported in an individual meeting revised Bethesda criteria who was diagnosed with colon cancer at the age of 47 and had secondary neoplasia diagnosed at 47 as well as 48. Tumor analysis showed MSI-H and loss of MSH6 by IHC (Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). This alteration was also identified in an individual diagnosed with colon cancer at the age of 38, but had no family history of cancer. Although he did not fulfill Amsterdam II criteria, IHC tumor analysis showed isolated loss of MSH6 (Talseth-Palmer B.A. et al. Hered Cancer Clin Pract 2010;8(1):5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at