Submissions for variant NM_000251.2(MSH2):c.2425G>A (p.Glu809Lys) (rs202145681)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129519	SCV000184295	likely benign	Hereditary cancer-predisposing syndrome	2018-12-11	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae	RCV001080801	SCV000260613	benign	Hereditary nonpolyposis colorectal neoplasms	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000121564	SCV000515732	likely benign	not specified	2017-10-16	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.
Color	RCV000129519	SCV000685041	likely benign	Hereditary cancer-predisposing syndrome	2016-05-30	criteria provided, single submitter	clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research	RCV001030484	SCV001193638	uncertain significance	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Integrated Genetics/Laboratory Corporation of America	RCV000121564	SCV001363056	benign	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2425G>A (p.Glu809Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251372 control chromosomes, predominantly at a frequency of 0.0038 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold 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.2425G>A has been reported in the literature in individuals affected with Lynch Syndrome (Jiang_2019, Liu_2014, Pinard_2016, Tang_2009, Toh_2018, Xie_2018), predominantly in individuals of Asian origin. A database cites the variant to co-occur with a pathogenic variant in MSH2 (c.942+3A>T) and indicated that the variant did not cosegregate with disease in a family. Four ClinVar submissions (evaluation after 2014) cite the variant three times as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034556	SCV000043346	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121564	SCV000085758	not provided	not specified	2013-09-19	no assertion provided	reference population
Ding PR Lab,Sun Yat-sen University Cancer Center	RCV001093691	SCV001250875	uncertain significance	Lynch syndrome I		no assertion criteria provided	clinical testing