rs587781924
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.3311_3312del(p.Phe1104TrpfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 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. T1102T) has been classified as 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.3311_3312del | p.Phe1104TrpfsTer3 | frameshift_variant | 5/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3311_3312del | p.Phe1104TrpfsTer3 | frameshift_variant | 5/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 04, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 14, 2021 | This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, it has been described in individuals with endometrial cancer, ovarian cancer, and colorectal cancer in the published literature (PMID: 33746161 (2021), 30128536 (2018), 26648449 (2015), 23541221 (2013), 12376742 (2002)). Based on the available information, this variant is classified as pathogenic. - |
Lynch syndrome 5 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 22, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This variant deletes 2 nucleotides in exon 5 of the MSH6 gene, creating a frameshift and 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-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 chromosomes 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 - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This variant deletes 2 nucleotides in exon 5 of the MSH6 gene, creating a frameshift and 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-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 chromosomes 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, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2023 | The c.3311_3312delTT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3311 to 3312, causing a translational frameshift with a predicted alternate stop codon (p.F1104Wfs*3). This variant was described in a proband with ovarian cancer at 49 years of age, whose family history included a father with rectal cancer at 80 years and paternal first cousin with endometrial cancer at 57 years. The proband's cousin was confirmed to be positive for the variant, which established obligate carrier status in the proband's father (Suchy J et al. J. Hum. Genet. 2002;47:529-31; Suchy J et al. Clin Genet. 2006 Jul;70:68-70). This variant was also reported in a man with MSI-H colorectal cancer diagnosed at age 22 and no family history; this individual also carried an alteration in HOXB13 (p.G84E) (Akbari MR et al. Cancer Epidemiol. 2013 Aug;37(4):424-7). The c.3311_3312delTT variant has also been reported in a 60 year old woman with three synchronous primary malignancies and whose family history met Amsterdam II criteria (Mendez LE et al. Gynecol Oncol Rep. 2016 Aug;17:29-32). 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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | This sequence change creates a premature translational stop signal (p.Phe1104Trpfs*3) 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 present in population databases (rs267608092, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 89370). For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 25, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at