rs1060502886
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):βc.1815_1816delβ(p.Lys606AsnfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. T605T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1815_1816del | p.Lys606AsnfsTer33 | frameshift_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1815_1816del | p.Lys606AsnfsTer33 | frameshift_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461876Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2023 | The c.1815_1816delTA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 1815 to 1816, causing a translational frameshift with a predicted alternate stop codon (p.K606Nfs*33). This mutation was identified in an HNPCC family from Latvia (Irmejs A et al. Hered Cancer Clin Pract. 2003;1(1):49–53). 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 | Jan 15, 2020 | 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 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:1
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. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2022 | Variant summary: MSH6 c.1815_1816delTA (p.Lys606AsnfsX33) 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. The variant was absent in 250498 control chromosomes (gnomAD). c.1815_1816delTA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) associated tumors, including one proband who was also noted to meet the Amsterdam II criteria for late onset HNPCC (e.g. Irmejs_2003, Maccaroni_2015, Waszak_2018, Dong_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
MSH6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 27, 2023 | The MSH6 c.1815_1816delTA variant is predicted to result in a frameshift and premature protein termination (p.Lys606Asnfs*33). This variant was reported in an individual with colorectal cancer (described as c.1815delTA T605fsX638 in Table 2 in Maccaroni et al 2015. PubMed ID: 26485756) and in an individual with medulloblastoma (Supplementary Table 2 in Waszak SM et al 2018. PubMed ID: 29753700). In ClinVar, this variant is interpreted as pathogenic by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/410412/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2016 | This deletion of two nucleotides in MSH6 is denoted c.1815_1816delTA at the cDNA level and p.Lys606AsnfsX33 (K606NfsX33) at the protein level. The normal sequence, with the bases that are deleted in braces, is AAAC[TA]AAAC. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 606, and creates a premature stop codon at position 33 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.1815_1816delTA, also denoted MSH6 c.1815delTA using alternative nomenclature, has been observed at least once, in an individual with colorectal cancer who met Bethesda Guidelines (Maccaroni 2015). We consider this variant to be pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change creates a premature translational stop signal (p.Lys606Asnfs*33) 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 (PMID: 26485756). ClinVar contains an entry for this variant (Variation ID: 410412). For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at