Submissions for variant NM_000251.2(MSH2):c.2205C>T (p.Ile735=) (rs533553381)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212617	SCV000170347	benign	not specified	2013-12-27	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	RCV000126821	SCV000212951	likely benign	Hereditary cancer-predisposing syndrome	2014-09-16	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.
Illumina Clinical Services Laboratory,Illumina	RCV000323210	SCV000430933	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000409899	SCV000488353	likely benign	Lynch syndrome I	2016-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV001083829	SCV000559194	benign	Hereditary nonpolyposis colorectal neoplasms	2020-12-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212617	SCV000601460	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000126821	SCV000685022	benign	Hereditary cancer-predisposing syndrome	2015-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590738	SCV000696238	benign	not provided	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.2205C>T (p.Ile735Ile) 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 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 185/121382 control chromosomes (2 homozygotes), predominantly observed in the South Asian subpopulation at a frequency of 0.0109038 (180/16508). This frequency is about 19 times 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 South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. One internal sample also carried a disease variant in BRCA1 c.3869_3870delAA, further suppporting the benign classification. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics	RCV000212617	SCV000806027	benign	not specified	2017-07-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000212617	SCV000592543	benign	not specified		no assertion criteria provided	clinical testing	The p.Ile735Ile 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. The variant was identified in the ClinVar database, where it was classified as “benign” by GeneDX and as “likely benign” by Ambry Genetics. The variant was not identified in any of the other databases searched (dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, GeneInsight COGR database, and UMD). The variant was identified in an individual tested by our laboratory in a hemizygous state, with a co-occuring pathogenic MSH2 deletion of exons 12-16 in trans, increasing the likelihood that the variant does not have clinical significance. In summary, based on the above information this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212617	SCV000691910	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126821	SCV000805269	likely benign	Hereditary cancer-predisposing syndrome	2018-05-09	no assertion criteria provided	clinical testing