ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.704_705del (p.Lys235fs) (rs281864944)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076686 SCV000107721 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000484029 SCV000568623 pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH2 is denoted c.704_705delAA at the cDNA level and p.Lys235ArgfsX20 (K235RfsX20) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACAA[AA]GACA. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 235, and creates a premature stop codon at position 20 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. MSH2 c.704_705delAA has been identified in association with colon cancer (Syngal 1999, Mangold 2005). We consider this variant to be pathogenic.
Ambry Genetics RCV000491296 SCV000580443 pathogenic Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000076686 SCV000696280 pathogenic Lynch syndrome 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.704_705delAA (p.Lys235Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 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.1030C>T/ p.Gln344X; c.1147C>T/ p.Arg383X; c.1165C>T/ p.Arg389X; c.1189C>T/ p.Gln397X). In addition, the variant of interest has been reported as pathogenic in multiple affected individuals via publications (Mangold_IJC_2005; Syngal_MLH1_JAMA_1999) and in one reputable database. One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121020 control chromosomes. Taken together, this variant is classified as pathogenic.
Invitae RCV000688140 SCV000815741 pathogenic Hereditary nonpolyposis colon cancer 2019-06-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys235Argfs*20) in the MSH2 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 suspected of having Lynch syndrome (PMID: 10422993, 15849733). ClinVar contains an entry for this variant (Variation ID: 91182). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000076686 SCV000967752 pathogenic Lynch syndrome 2018-03-09 criteria provided, single submitter clinical testing The p.Lys235fs variant in MSH2 has been reported in 3 individuals with Lynch syn drome-associated cancers (Mangold 2005, Syngal 1999) and been identified in 1/11 1640 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno; dbSNP rs281864944). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 235 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozy gous loss of function of the MSH2 gene is an established disease mechanism in in dividuals with Lynch syndrome. In addition, this variant was classified as patho genic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV00 0107721.2). In summary, this variant meets criteria to be classified as pathogen ic for Lynch syndrome in an autosomal dominant manner based upon presence in mul tiple affected individuals, low frequency in the general population, and the pre dicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; P M2; PS4_Supporting.
Color RCV000491296 SCV001354532 pathogenic Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing

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