ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2230dup (p.Glu744fs) (rs786201050)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162451 SCV000212804 pathogenic Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000162451 SCV000685267 pathogenic Hereditary cancer-predisposing syndrome 2016-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000221977 SCV000279101 pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.2230dupG at the cDNA level and p.Glu744GlyfsX12 (E744GfsX12) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTTG[dupG]AGAT. The duplication causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 744 and creates a premature stop codon at position 12 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.2230dupG has been reported in association with Lynch syndrome (Ward 2013, Brand 2018, Chan 2018). We consider this variant to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778100 SCV000430969 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2018-05-04 criteria provided, single submitter clinical testing The MSH6 c.2230dupG (p.Glu744GlyfsTer12) variant, also reported as c.2228_2229insG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Glu744GlyfsTer12 variant has been reported in two studies and is found in a compound heterozygous state in two probands with colorectal cancer (Ward et al. 2013; DeRycke et al. 2017). The variant is reported at a frequency of 0.000016 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants and evidence from literature, the p.Glu744GlyfsTer12 variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000198617 SCV000695803 pathogenic Lynch syndrome 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2230dupG (p.Glu744Glyfs) 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. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121164 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was reprted in a colorectal cancer patient who had family history of the disease indicating pathogenicity. Moreover, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg911X, p.Arg1035X) further supporting a deleterious outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000524135 SCV000255260 pathogenic Hereditary nonpolyposis colon cancer 2018-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu744Glyfs*12) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs773290953, ExAC 0.002%). This variant has been reported in an individual affected with colorectal cancer (PMID: 23733757). ClinVar contains an entry for this variant (Variation ID: 183739). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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