ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3850dup (p.Thr1284fs) (rs1553333421)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000583214 SCV000690414 pathogenic Hereditary cancer-predisposing syndrome 2020-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000657421 SCV000779156 pathogenic not provided 2020-11-16 criteria provided, single submitter clinical testing 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 in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Reported as a pathogenic variant in healthy individuals enrolled in screening studies (Capalbo 2019, eMERGE Consortium 2019); This variant is associated with the following publications: (PMID: 31447099, 31589614)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657421 SCV000889497 likely pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501318 SCV000917748 likely pathogenic Lynch syndrome 2017-12-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3850dupA (p.Thr1284AsnfsX5) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. A variant that affects the same codon and leads to an equivalent change at the protein level (c.3847_3850dupATTA (p.Thr1284Asnfs)) as the variant of interest has been classified as pathogenic by multiple laboratories. Also, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3938_3941dupTTCA (p.Gln1314fsX6), c.3939_3957dupTCAAAAGGGACATAGAAAA (p.Ala1320fsX5), c.3939_3940dupTC (p.Gln1314fsX14)). This variant is absent in 276776 control chromosomes. In addition, one diagnostic laboratory classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV001380321 SCV001578324 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-07-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1284Asnfs*5) 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). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 433926). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353784 SCV000592657 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Thr1284AsnfsX5 variant was not identified in the literature nor was it identified in the dbSNP, Clinvitae, COSMIC, Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, InSiGHT Colon Cancer Gene Variant (LOVD), Zhejiang Colon Cancer (LOVD), ClinVar, GeneInsight - COGR and UMD databases. The variant was also not identified in the 1000 Genomes Project, NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.3850dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1284 and leads to a premature stop codon 5 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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