ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1680T>C (p.Asn560=) (rs200056411)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076241 SCV000107260 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effec on splicing, tested with NMD inhibitor
GeneDx RCV000212605 SCV000170343 benign not specified 2013-12-18 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 RCV000126817 SCV000212795 likely benign Hereditary cancer-predisposing syndrome 2014-07-07 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 RCV001081918 SCV000253152 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986677 SCV000430929 uncertain significance Lynch syndrome I 2018-01-12 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212605 SCV000601435 benign not specified 2017-06-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000126817 SCV000684966 benign Hereditary cancer-predisposing syndrome 2015-07-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587483 SCV000696222 benign not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1680T>C (p.Asn560Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict no change to normal splicing, and ex vivo splicing assay showed this variant does not affect splicing. This variant was found in 42/120644 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0006173 (41/66422). This frequency is greater than the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, the variant was found to co-occur with a pathogenic MSH2 variant, c.1079T>A (p.Leu360X), in one individual reported by UMD. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587483 SCV000889422 benign not provided 2017-06-07 criteria provided, single submitter clinical testing
Mendelics RCV000986677 SCV001135740 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587483 SCV001152278 likely benign not provided 2021-05-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355862 SCV001550868 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Asn560= variant was identified in the literature however the frequency of this variant in an affected population was not provided (Tournier 2008). The variant was also identified in the following databases: dbSNP (ID: rs200056411) as With Likely benign allele, ClinVar (classified as benign by GeneDx, Invitae; as likely benign by Insight, Ambry Genetics), Clinvitae (classified as benign by ClinVar; as likely benign by Invitae), UMD-LSDB (6X as neutral), Insight Colon Cancer Gene Variant Database (8X Class2), and the Insight Hereditary Tumors Database (8X Class2). The variant was not identified in COGR, Zhejiang Colon Cancer Database, and Mismatch Repair Genes Variant Database. In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.1079T>A (p.Leu360X)), increasing the likelihood that the p.Asn560= variant does not have clinical significance. The variant was identified in control databases in 81 of 276170 chromosomes at a frequency of 0.0003 in the following populations: EuropeanNon-Finnish in 71 of 126188 chromosomes (freq. 0.001), EuropeanFinnish in 6 of 25786 chromosomes (freq. 0.0002), Latino in 2 of 34356 chromosomes (freq.0.0001), African in 1 of 24008 chromosomes (freq. 0.00004), Other in 1 of 6452 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). Functional analysis using the pCAS ex vivo splicing assay demonstrated this variant had no effect (Tournier 2008). The p.Asn560= 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, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000587483 SCV001807293 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000587483 SCV001905768 likely benign not provided no assertion criteria provided clinical testing

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