ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2766T>C (p.Phe922=) (rs55859129)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490569 SCV000107573 benign Lynch syndrome I 2014-10-10 reviewed by expert panel research MAF >1%
Invitae RCV000524398 SCV000153820 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129755 SCV000184562 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000490569 SCV000430937 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 RCV000129755 SCV000685071 benign Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000202259 SCV000806036 benign not specified 2017-03-20 criteria provided, single submitter clinical testing
GeneDx RCV001646998 SCV001858925 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202259 SCV000257183 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000129755 SCV000788035 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355980 SCV001551020 benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Phe922= variant was identified in 1 of 70 proband chromosomes (frequency: 0.01) from Portuguese individuals or families with HNPCC and was not identified in 400 control chromosomes from healthy individuals (Isidro_2003_14517962). In addition, mRNA analysis showed the variant yielded no alternative transcripts, and segregation studies showed the variant was found in both affected and unaffected family members (Isidro_2003_14517962). The variant was also identified in dbSNP (ID: rs55859129) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (2014); submitters: benign by InSIGHT, Invitae, Ambry Genetics and Mayo Clinic, and likely benign by Illumina), Clinvitae (4x), UMD-LSDB (4x as neutral, co-occurring with a pathogenic MSH6 variant (c.2150_2153delTCAG (p.Val717AlafsX18)), Insight Colon Cancer Gene Variant Database (3x as class 1), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database, and was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1074 (14 homozygous) of 274470 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 989 (14 homozygous) of 23868 chromosomes (freq: 0.04), Other in 7 of 6412 chromosomes (freq: 0.001), Latino in 71 of 34118 chromosomes (freq: 0.002), European Non-Finnish in 7 of 125698 chromosomes (freq: 0.00006), while not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Phe922= 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.
Clinical Genetics,Academic Medical Center RCV000202259 SCV001917207 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000202259 SCV001959265 benign not specified no assertion criteria provided clinical testing

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