chr2-47799151-GAT-AA
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.1168_1170delGATinsAA(p.Asp390AsnfsTer21) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D390Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift, missense
Scores
Clinical Significance
Conservation
Publications
- intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.1168_1170delGATinsAA | p.Asp390AsnfsTer21 | frameshift_variant, missense_variant | Exon 4 of 10 | ENST00000234420.11 | NP_000170.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.1168_1170delGATinsAA | p.Asp390AsnfsTer21 | frameshift_variant, missense_variant | Exon 4 of 10 | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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 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; Identified in healthy individuals undergoing clinical exome sequencing in published literature (Grzymski 2020); This variant is associated with the following publications: (PMID: 32719484) -
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This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported among a cohort individuals with hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia (PMID: 32719484 (2020)). Therefore, the variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 3 nucleotides and inserts 2 new 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. To our knowledge, this variant has not been reported in individuals affected with MSH6-related disorders in the literature. 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. -
The c.1168_1170delGATinsAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from the deletion of 3 nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.D390Nfs*21). This alteration has been identified in several individuals with MSH6-deficient colon or endometrial cancers and/or whose family history meets Amsterdam I/II criteria (Ambry internal data; Lucas E et al. Int J Gynecol Pathol. 2019 Nov;38:533-542). This alteration was also identified in a Hispanic female diagnosed with endometrial adenocarcinoma with equivocal MSH2 and MSH6 expression on IHC and a metachronous peritoneal mesothelioma 10 months later (Lu Y et al. Int J Surg Pathol. 2017 May;25:253-257). 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. -
Lynch syndrome 5 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH6 c.1168_1170delinsAA (p.Asp390AsnfsX21) 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 251000 control chromosomes. To our knowledge, no occurrence of c.1168_1170delinsAA in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, the variant was reported once among 29,606 participants in the Healthy Nevada Project (HNP) that aimed to identity carriers of autosomal dominant diseases by population screening (example, Grzymski_2020). It is not specified whether this individual had clinically relevant disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic. -
Lynch syndrome Pathogenic:1
This variant deletes 3 nucleotides and inserts two new 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. To our knowledge, this variant has not been reported in individuals affected with MSH6-related disorders in the literature. 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. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp390Asnfs*21) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with undergoing testing for Lynch syndrome (PMID: 30927264). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 218051). For these reasons, this variant has been classified as Pathogenic. -
Endometrial carcinoma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at