rs864622153
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000179.3(MSH6):c.1691C>A(p.Ser564Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 Likely pathogenic (★★). 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.1691C>A | p.Ser564Ter | stop_gained | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1691C>A | p.Ser564Ter | stop_gained | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome 5 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 12, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 28, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2017 | This variant is denoted MSH6 c.1691C>A at the cDNA level and p.Ser564Ter (S564X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in an individual tested on a hereditary colorectal cancer panel (Ferber 2016). We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 16, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2021 | The p.S564* pathogenic mutation (also known as c.1691C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1691. This changes the amino acid from a serine to a stop codon within coding exon 4. This mutation has been detected in multiple endometrial cancer patients whose tumors demonstrated loss of MSH6 on immunohistochemistry (Ambry internal data). A different nucleotide change at this position (c.1691C>G) that leads to the same stop codon was seen in two Swedish families with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). 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 | Oct 01, 2021 | 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 observed in an individual affected with ovarian cancer (Color internal data). A different DNA substitution resulting in the same protein consequence (c.1691C>G; p.Ser564*) has been observed in two families affected with Lynch syndrome (PMID: 27601186). 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
MSH6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 21, 2022 | The MSH6 c.1691C>A variant is predicted to result in premature protein termination (p.Ser564*). This variant has been reported in an individual being tested on a hereditary colorectal cancer panel (Ferber et al. 2016. Journal of Medical Diagnostic Methods, vol 5). A different nucleotide variant (c.1691C>G) which also causes a premature termination codon at this position has been reported in individuals with Lynch syndrome (Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MSH6 are expected to be pathogenic. Given the evidence, we interpret c.1691C>A (p.Ser564*) as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 28, 2023 | This sequence change creates a premature translational stop signal (p.Ser564*) 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 Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 219551). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at