ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1691C>A (p.Ser564Ter) (rs864622153)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204908 SCV000259478 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). A different variant (c.1691C>G), giving rise to the same protein effect observed here (p.Ser564*), has been observed in several families with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 219551). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481005 SCV000570637 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000491176 SCV000580348 pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing 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. 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.
Counsyl RCV000576302 SCV000677830 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-12-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491176 SCV000690217 pathogenic Hereditary cancer-predisposing syndrome 2020-09-14 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481005 SCV000888247 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing
CZECANCA consortium RCV001270947 SCV001451751 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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