ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1560A>G (p.Gly520=) (rs63750820)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212603 SCV000170339 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 RCV000126813 SCV000213544 likely benign Hereditary cancer-predisposing syndrome 2014-07-18 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.
Invitae RCV000524346 SCV000253150 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662509 SCV000430925 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Health, Inc RCV000126813 SCV000537417 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212603 SCV000696217 likely benign not specified 2019-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000662509 SCV000785045 likely benign Lynch syndrome I 2017-03-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212603 SCV001469554 benign not specified 2019-11-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356577 SCV001551786 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Gly520= variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs63750820) as “With other allele”, ClinVar (classified as benign by GeneDx and Invitae, as likely benign by Ambry Genetics and Color Genomics, and as uncertain significance by Illumina Clinical Services), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (1x). The variant was not identified in COGR, COSMIC, MutDB, UMD-LSDB, or Zhejiang Colon Cancer databases. The variant was identified in control databases in 34 of 277178 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Ashkenazi Jewish in 29 of 10150 chromosomes (freq: 0.003), Other in 3 of 6464 chromosomes (freq: 0.0005), and European in 2 of 126680 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, East Asian, Finnish, or South Asian populations. In an in vitro study of mismatch repair efficiency, this variant demonstrated in tact MMR activity (Tronov 2006). The p.Gly520= 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, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder) predict that the variants creates a new 5’ splice site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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