ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2690dup (p.Asn897fs) (rs1553414010)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483177 SCV000568720 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.2690dupA at the cDNA level and p.Asn897LysfsX3 (N897KfsX3) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]TCCT. The duplication causes a frameshift which changes an Asparagine to a Lysine at codon 897, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2690dupA has been observed in at least one family with Lynch syndrome and in at least one individual with ovarian cancer (Baglietto 2010, Pal 2012). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503246 SCV000592612 pathogenic Lynch syndrome 2016-06-30 criteria provided, single submitter clinical testing
Invitae RCV000696931 SCV000825514 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-01-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn897Lysfs*3) 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 been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 20028993, Invitae) and with ovarian cancer (PMID: 23047549). This variant is also known as c.2690_2691insA in the literature. ClinVar contains an entry for this variant (Variation ID: 420121). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483177 SCV001134414 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics RCV001016324 SCV001177268 pathogenic Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV001016324 SCV001350147 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192426 SCV001360539 likely pathogenic Hereditary nonpolyposis colon cancer 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2690dupA (p.Asn897LysfsX3) 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 (e.g. c.2764C>T (p.Arg922X), c.3037_3041delAAGAA (p.Lys1013fsX3)). The variant was absent in 250556 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with cancer (Baglietto_2009, Pal_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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