ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.984C>T (p.Ala328=) (rs4987189)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076774 SCV000107813 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000192476 SCV000170333 benign not specified 2014-01-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000126809 SCV000212787 likely benign Hereditary cancer-predisposing syndrome 2014-06-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago RCV000192476 SCV000248075 benign not specified 2019-02-12 criteria provided, single submitter clinical testing
Invitae RCV001079823 SCV000252657 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000192476 SCV000303168 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000613302 SCV000430920 likely benign Lynch syndrome I 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Health, Inc RCV000126809 SCV000685147 benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000613302 SCV000744272 likely benign Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000613302 SCV000745636 likely benign Lynch syndrome I 2015-08-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000192476 SCV001158687 benign not specified 2019-02-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000192476 SCV000592483 benign not specified no assertion criteria provided clinical testing The MSH2 p.Ala328= variant was identified in 8 of 1632 proband chromosomes (frequency: 0.005) from Italian, Dutch, Australian and Chinese individuals or families suspected of having Lynch syndrome/meeting Amsterdam and/or Bethesda criteria, and was identified in 1 of 346 control chromosomes (frequency: 0.003) from healthy individuals (Pastrello_2011_21239990, Yap_2009_18726168, Curia_1999_10446963, Lee_2005_15996210, Scott_2001_11112663, Overbeek_2007_17453009, Samowitz_2001_11606497). The variant was also identified as a somatic mutation in a study of sporadic colon tumors of Hungarian patients (Kamory 2003). In 1 proband with an MSI+/ hypermethylation negative, IHC intact tumour, germline analysis identified the variant co-occurring with an unclassified variant c.250A4G (p.Lys84Glu) in MLH1 (Overbeek_2007_17453009), and in another study with a pathogenic MSH2 variant (c.942+2T>A) (Pastrello_2011_21239990). The variant was identified in the following databases: dbSNP (ID: rs4987189) “With Likely benign, other allele”, ClinVar (classified likely benign, reviewed by an expert panel (2013); submitters: benign by GeneDx, Invitae and Prevention Genetics, and likely benign by InSIGHT, Ambry Genetics, and Illumina), Clinvitae (3x), Cosmic (1x in a carcinoma of the large intestine), UMD-LSDB (6x as neutral, co-occurring with pathogenic variants MSH6 (c.2455G>T/p.Glu819X), and MLH1 (c.1489delC/ p.Arg497GlyfsX11, c.121G>C/p.Asp41His), Insight Colon Cancer Gene Variant Database (16x as class 2), Mismatch Repair Genes Variant Database (8x), Insight Hereditary Tumors Database (18x), and in control databases in 1270 (26 homozygous) of 277190 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 22 of 6468 chromosomes (freq: 0.003), Latino in 95 (1 homozygous) of 34416 chromosomes (freq: 0.003), European Non-Finnish in 212 of 126682 chromosomes (freq: 0.002), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 5 of 25786 chromosomes (freq: 0.0002), and South Asian in 926 (25 homozygous) of 30782 chromosomes (freq: 0.03). The variant was not identified in GeneInsight-COGR, MutDB, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 4 individuals with colon cancer. 1 pos case variant cooccurred with pathogenic msh2 mutation c.942+2T>Apos case malyasianunrelated healthy controls. The p.Ala328= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000613302 SCV000734198 likely benign Lynch syndrome I no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656570 SCV000778617 likely benign not provided 2017-12-18 no assertion criteria provided clinical testing
True Health Diagnostics RCV000126809 SCV000805271 likely benign Hereditary cancer-predisposing syndrome 2018-05-29 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000192476 SCV001918443 benign not specified no assertion criteria provided clinical testing

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