chr2-47798725-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.742C>T(p.Arg248Ter) variant causes a stop gained change involving the alteration of a non-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. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R248R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 stop_gained
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.742C>T | p.Arg248Ter | stop_gained | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.742C>T | p.Arg248Ter | stop_gained | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 30, 2023 | PP4, PP5, PM2, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal and/or family history of MSH6-related cancers (Wijnen 1999, Steinke 2008, Tsukanov 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 33087929, 33937060, 30787465, 10508506, 15236168, 12547705, 20028993, 18301448, 29625052, 28502729) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 25, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Lynch syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome, with tumor analyses showing microsatellite instability and/or loss of MSH6 protein by immunohistochemistry analyses (PMID: 10508506, 12547705, 18301448, 33937060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Arg248X variant in MSH6 has been previously reported in 1 individual with Lynch syndrome (Steinke 2008) and 2 individuals with colorectal cancer (Wijnen 1999, Hendricks 2003). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89563). This nonsense variant leads to a premature termination codon at position 248, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2021 | The p.R248* pathogenic mutation (also known as c.742C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 742. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in multiple individuals with Lynch syndrome-associated cancers (Wijnen J et al. Nat. Genet. 1999 Oct;23(2):142-4; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92; Chao X et al. Cancer Commun (Lond), 2019 07;39:42; Tsukanov AS et al. Front Oncol, 2021 Apr;11:652696). In one study, authors reported this pathogenic mutation in an individual diagnosed with colon cancer at age 26 whose tumor showed high microsatellite instability and absent MSH6 staining on IHC (Hendriks Y et al. Am. J. Pathol. 2003 Feb;162(2):469-77). Additionally, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome, with tumor analyses showing microsatellite instability and/or loss of MSH6 protein by immunohistochemistry analyses (PMID: 10508506, 12547705, 18301448, 33937060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Lynch syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 10, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2023 | Variant summary: MSH6 c.742C>T (p.Arg248X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.892C>T, p.Arg298X; c.1135_1139delAGAGA, p.Arg379X; c.1190_1191delAT, p.Tyr397fsX3). The variant was absent in 276846 control chromosomes (gnomAD). c.742C>T has been reported in the literature in individuals affected with Lynch Syndrome; analysis of tumor samples showed loss of MSH6 protein expression via immunohistochemistry and high microsatellite instability (Tsukanov_2021, Steinke_2008, Hendriks_2003, Wijnen_1999). These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12547705, 15236168, 28152038, 18301448, 33937060, 10508506). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89563). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10508506, 18301448). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg248*) 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). - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 22, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at