Submissions for variant NM_000251.2(MSH2):c.1886A>G (p.Gln629Arg) (rs61756468)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076314	SCV000107335	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV001079970	SCV000166267	benign	Hereditary nonpolyposis colorectal neoplasms	2020-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000587872	SCV000170345	benign	not provided	2018-11-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24933000, 22995991, 22283331, 22949387, 29506494, 27487738, 15365995, 21155023, 22290698, 20965939, 23760103, 24728327, 12132870, 26332594, 25985138, 24078570, 29642919, 15996210, 16929514, 18257912, 18383312, 18636359, 18726168, 24396821, 28580595)
Ambry Genetics	RCV000129036	SCV000172946	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center	RCV000490519	SCV000267400	uncertain significance	Lynch syndrome I	2016-03-18	criteria provided, single submitter	reference population
Illumina Clinical Services Laboratory,Illumina	RCV000490519	SCV000430930	likely benign	Lynch syndrome I	2017-04-27	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121562	SCV000601445	likely benign	not specified	2016-10-12	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000129036	SCV000684992	benign	Hereditary cancer-predisposing syndrome	2015-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587872	SCV000696228	benign	not provided	2016-09-06	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1886A>G (p.Gln629Arg) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 159/123118 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0174486 (151/8654). This frequency is about 31 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 East Asian origin. This variant has also been reported in colorectal patients or HNPCC-related cancer without strong evidence for pathogenicity. In a family, while affected proband carried the variant, another affected cousin did not carry the variant, possibly suggesting that it did not co-segregate with disease in the family (Woo_2014). Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000490519	SCV000745643	benign	Lynch syndrome I	2017-07-04	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000121562	SCV000806016	benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000587872	SCV001502301	uncertain significance	not provided	2020-09-01	criteria provided, single submitter	clinical testing
ITMI	RCV000121562	SCV000085756	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000121562	SCV000691907	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001355305	SCV001550157	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Gln629Arg variant was identified in 8 of 882 proband chromosomes (frequency: 0.009) from individuals or families with colon cancer, gastric cancer, and hepatocellular carcinoma (Jin 2008, Lee 2005, Lim 2010, Shin 2004, Wang 2006, Yano 2007, Yap 2009, Zhang 2006). Yuan (2004) also found the variant in 7 of 200 chromosomes in unaffected individuals (freq 0.035), and therefore classified the variant as a polymorphism. The variant was also identified in dbSNP (ID: rs61756468) as “With Uncertain significance allele”, ClinVar (as benign, reviewed by an expert panel), Clinvitae (as benign), Cosmic, Insight Colon Cancer Gene Variant Database (reported 19x as benign), Zhejiang Colon Cancer Database (reported 6x), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, MMR Gene Unclassified Variants Database. The variant was identified in control databases in 317 of 277184 chromosomes at a frequency of 0.0011 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 304 (1 homozygous) of 18870 chromosomes (freq: 0.01611), Other in 2 of 6464 chromosomes (freq: 0.000309), European (Non-Finnish) in 1 of 126690 chromosomes (freq: 0.000008), European (Finnish) in 3 of 25786 chromosomes (freq: 0.000116), and South Asian in 7 of 30782 chromosomes (freq: 0.000227), while the variant was not observed in the African, Latino, or Ashkenazi Jewish populations. The p.Gln629 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics,Academic Medical Center	RCV000121562	SCV001919028	benign	not specified		no assertion criteria provided	clinical testing