2-47799613-GAAAA-GAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):βc.1634_1635delβ(p.Lys545ArgfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E544E) 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.1634_1635del | p.Lys545ArgfsTer17 | frameshift_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1634_1635del | p.Lys545ArgfsTer17 | frameshift_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | Frameshift 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; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with Lynch syndrome-associated cancer and/or colon polyps (Yurgelun et al., 2015; Ring et al., 2016); This variant is associated with the following publications: (PMID: 28888541, 26681312, 21674763, 28152038, 25980754, 27443514, 30787465, 33087929, 19194194) - |
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 | Feb 26, 2015 | - - |
Lynch syndrome 5 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 15, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Lynch syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 30, 2023 | This variant deletes 2 nucleotides in exon 4 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 observed in individuals affected with suspected Lynch syndrome (PMID: 25980754 ), colorectal cancer (PMID: 26681312), and endometrial cancer (PMID: 27443514). 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, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2024 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2022 | This variant deletes 2 nucleotides in exon 4 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 observed in individuals with suspected Lynch syndrome (PMID: 25980754 ), colorectal cancer (PMID: 26681312), and endometrial cancer (PMID: 27443514). 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, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2021 | The c.1634_1635delAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 2 nucleotides at positions 1634 and 1635 causing a translational frameshift with a predicted alternate stop codon (p.K545Rfs*17). This alteration was previously reported in trans with another MSH6 pathogenic mutation in a child with constitutional mismatch repair deficiency (CMMR-D) syndrome (Peters A et al. J. Pediatr. Hematol. Oncol. 2009 Feb;31(2):113-5). 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. - |
MSH6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 23, 2023 | The MSH6 c.1634_1635delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys545Argfs*17). This variant has been reported in a cohort of individuals with suspected Lynch syndrome (Table S1 - Yurgelun et al. 2015. PubMed ID: 25980754). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140961/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change creates a premature translational stop signal (p.Lys545Argfs*17) 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 colorectal cancer and lymphoblastic lymphoma (PMID: 19194194, 26681312). ClinVar contains an entry for this variant (Variation ID: 140961). For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at