ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3753_3756dup (p.Val1253fs) (rs876661222)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216513 SCV000279830 pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing This duplication of four nucleotides in MSH6 is denoted c.3753_3756dupATTA at the cDNA level and p.Val1253IlefsX23 (V1253IfsX23) at the protein level. The normal sequence, with the bases that are duplicated in braces, is ATTC[ATTA]GTAG. The duplication causes a frameshift, which changes a Valine to an Isoleucine at codon 1253, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics RCV000566381 SCV000662520 pathogenic Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing The c.3753_3756dupATTA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of ATTA at nucleotide position 3753, causing a translational frameshift with a predicted alternate stop codon (p.V1253Ifs*23). 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 RCV000576807 SCV000677835 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-01-16 criteria provided, single submitter clinical testing
Invitae RCV000690322 SCV000818004 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1253Ilefs*23) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234794). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000502952 SCV000837921 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000576807 SCV001135847 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353594 SCV000592655 pathogenic Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.Val1253IlefsX23 variant was not identified in the literature nor was it identified in dbSNP, (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight COGR database, and UMD. The c.3753_3756dupATTA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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