ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1748A>G (p.Asn583Ser) (rs201118107)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034553 SCV000149419 likely benign not provided 2021-03-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25637381, 23047549, 22703879, 12658575, 18383312, 26898890, 27153395, 27600092, 26333163, 27720647, 30998989, 31159747)
Ambry Genetics RCV000115510 SCV000186283 likely benign Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000076263 SCV000257654 uncertain significance Lynch syndrome 2015-06-05 criteria provided, single submitter clinical testing
Invitae RCV001079601 SCV000262297 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034553 SCV000601439 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034553 SCV000806011 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115510 SCV000822047 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765667 SCV000897009 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115510 SCV000910730 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034553 SCV001152281 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034553 SCV000043343 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148636 SCV000190351 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354468 SCV001549093 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Asn583Ser variant was identified in 3 of 1836 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, colon cancer, and atherosclerosis (Caminsky 2016, Johnston 2012, Wagner 2003). The variant was also identified in dbSNP (ID: rs201118107) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx and 5 clinical laboratories; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (classified as uncertain significance by ClinVar; classified as likely benign by Invitae), UMD-LSDB (3x as unclassified variant), and the Insight Hereditary Tumors Database. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant c.1852_1854delAAG (p.Lys618del), increasing the likelihood that the p.Asn583Ser variant does not have clinical significance. In addition, a study by Wagner 2003 found this variant co-occurring with the MLH1 likely pathogenic variant c.589-1G>T. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 28 of 276902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 24012 chromosomes (freq: 0.0002), Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 4 of 34414 chromosomes (freq: 0.0001), European in 15 of 126460 chromosomes (freq: 0.0001), East Asian in 1 of 18862 chromosomes (freq: 0.0001), Finnish in 1 of 25788 chromosomes (freq: 0.00004), and South Asian in 1 of 30760 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish population. The p.Asn583 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. This information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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