ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3569_3572del (p.Ala1190fs) (rs267608120)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074956 SCV000108171 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000215904 SCV000273693 pathogenic Hereditary cancer-predisposing syndrome 2019-05-05 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000411917 SCV000489342 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-09-21 criteria provided, single submitter clinical testing
Invitae RCV000524198 SCV000551155 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Ala1320Glufs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the MSH6 protein. This variant is present in population databases (rs267608119, ExAC 0.002%). This variant has been observed in individuals and families affected with Lynch syndrome, and is considered a founder mutation in the Ashkenazi Jewish population (PMID: 12732731, 21155762, 20028993, 24440087, 23990280, 25430799, 20007843, 26544533). This variant is also known as 3956_3959delAAGC in the literature. ClinVar contains an entry for this variant (Variation ID: 89488). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000485556 SCV000566279 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing This deletion of four nucleotides in MSH6 is denoted c.3959_3962delCAAG at the cDNA level and p.Ala1320GlufsX6 (A1320EfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAG[delCAAG]AGAA. The deletion causes a frameshift, which changes an Alanine to a Glutamic Acid at codon 1320, and creates a premature stop codon at position 6 of the new reading frame, resulting in the last 41 correct amino acids being replaced by 5 incorrect ones. This frameshift is predicted to cause loss of normal protein function through protein truncation. MSH6 c.3959_3962delCAAG has been observed in several individuals with Lynch syndrome, has been reported in the compound heterozygous state in one family with three individuals with Constitutional Mismatch Repair Deficiency (CMMR-D), and is published as an Ashkenazi Jewish founder variant (Goodfellow 2003, Raskin 2011, Baris 2016). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074956 SCV000592665 pathogenic Lynch syndrome 2015-06-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485556 SCV000601592 pathogenic not provided 2016-07-25 criteria provided, single submitter clinical testing
Color RCV000215904 SCV000685467 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074956 SCV000695902 pathogenic Lynch syndrome 2016-07-05 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3959_3962delCAAG (p.Ala1320Glufs) 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. If this variant escapes NMD, it is expected to truncate P-loop containing nucleoside triphosphate hydrolase. Other similar truncations variants in this gene have been classified as pathogenic by our laboratory (e.g. p.Ala1320fs). This variant is absent in 122768 control chromosomes. This variant has been reported in literature as a pathogenic variant found in several patients with Lynch syndrome related cancers (Goodfellow_2003, Raskin_2015). It is regarded as a founder mutation in Ashkenazi Jews. Multiple clinical labs/reputable databases have classified it as pathogenic. Taken together, this variant is classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000411917 SCV000781796 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074956 SCV000966976 pathogenic Lynch syndrome 2018-03-09 criteria provided, single submitter clinical testing The p.Ala1320fs variant in MSH6 has been reported in at least 15 individuals wit h Lynch Syndrome-associated cancers (Goodfellow 2003, Hampel 2005, Raskin 2011, Goldberg 2014, Yurgelun 2015) and is believed to be an Ashkenazi Jewish founder variant (Raskin 2011). It has also been reported in the compound heterozygous st ate in one family with constitutional mismatch repair deficiency syndrome, where the variant was identified in 3 siblings who also had a second pathogenic varia nt in MSH6 (Bakry 2014). This variant has been identified in 3/9796 Ashkenazi Je wish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs267608120). This variant is predicted to cause a frameshi ft, which alters the protein?s amino acid sequence beginning at position 1320 an d leads to a premature termination codon 6 amino acids downstream. Although nons ense mediated decay is generally less likely to occur at this position (within t he terminal 50 bases of the penultimate exon), tumors from two patients with thi s variant have been found to have loss of MSH6 protein expression (Raskin 2011, Bakry 2014). Heterozygous loss of function of the MSH6 gene is an established di sease mechanism in individuals with Lynch syndrome. Additionally, this variant h as been classified as pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGH T expert panel (SCV000108171.2). In summary, this variant meets criteria to be c lassified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon presence in multiple affected individuals, very low frequency in the gener al population, functional evidence. ACMG/AMP Criteria applied (Richards 2015): P S4, PS3, PM2, PM4.

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