Submissions for variant NM_000251.2(MSH2):c.505A>G (p.Ile169Val) (rs63750716)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076619	SCV000107654	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000212588	SCV000149444	likely benign	not specified	2017-09-05	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.
Invitae	RCV001086693	SCV000166283	benign	Hereditary nonpolyposis colon cancer	2019-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115535	SCV000183948	likely benign	Hereditary cancer-predisposing syndrome	2018-11-30	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification;Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance)
Color	RCV000115535	SCV000537440	likely benign	Hereditary cancer-predisposing syndrome	2015-02-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212588	SCV000601482	benign	not specified	2017-06-22	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000659879	SCV000781770	uncertain significance	Lynch syndrome I	2016-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759836	SCV000889441	benign	not provided	2017-06-22	criteria provided, single submitter	clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research	RCV001030707	SCV001193629	likely benign	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000659879	SCV001297031	likely benign	Lynch syndrome I	2018-02-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America	RCV000212588	SCV001360857	benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.505A>G (p.Ile169Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251484 control chromosomes, predominantly at a frequency of 0.0064 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.505A>G has been reported in the literature in individuals affected with colon cancer and gastric cancer (Tomita_2003, Park_2008, Kim_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, Park_2008 reports that this variant did not co-segregate with disease in one family. Co-occurrence with a pathogenic variant has been reported (MSH2 c.905T>A, p.Leu302Ter) (Tomita_2003), providing supporting evidence for a benign role. At least one publication reports this variant showed no damaging effect of this variant (Zhu_2013). Six ClinVar submitters including one expert panel (InSiGHT, classified as likely benign in 2013) (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (3x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.