ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1168C>T (p.Leu390Phe) (rs17224367)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076053 SCV000107066 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078420 SCV000110269 benign not specified 2013-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000078420 SCV000149404 benign not specified 2018-02-20 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 RCV000115495 SCV000172768 benign Hereditary cancer-predisposing syndrome 2014-08-11 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV001081498 SCV000261493 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094729 SCV000430923 likely benign Lynch syndrome I 2018-03-06 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000078420 SCV000539680 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2.1% in East Asian population with 2 homozygotes.
Color Health, Inc RCV000115495 SCV000684912 benign Hereditary cancer-predisposing syndrome 2015-04-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034549 SCV000696199 benign not provided 2016-03-21 criteria provided, single submitter clinical testing Variant summary: The c.1168C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 229/123604 control chromosomes (2 homozygotes) at a frequency of 0.0018527. The frequency of this variant in East Asian control population is 0.0217, which is about 38 times of the maximal expected frequency of a pathogenic allele (0.0005683), suggesting this variant is benign. This variant has been reported in a large number of patients with LS or endometrial cancer. Two co-occurrences with a pathogenic variant (MLH1, c.2157dup, p.Val720Cysfs*3 and MSH2 c.196-187dupG, respectively) were reported, along with a reported lack of co-segregation with the disease (Okamura_1998). Multiple functional studies showed that MSH2 p.L390F has similar activity to wild-type MSH2. In addition, multiple clinical laboratories/reputable databases classified this variant as benign. Taken together, this variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000078420 SCV000805991 benign not specified 2017-04-04 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034549 SCV000043339 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000078420 SCV000085763 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355669 SCV001550619 benign Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Leu390Phe variant was identified in 12 of 952 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Jin 2008, Lee 2005, Wei 2011, Yap 2009, Zhang 2006) and was present in 1 of 220 control chromosomes (frequency: 0.005) from healthy individuals (Zhang 2006). The variant was also identified in dbSNP (ID: rs17224367) as With other allele, ClinVar (classified as benign by InSight, Emory Genetics, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Illumina, LMMPHCPM; classified as uncertain significance by BLDSNIH), Clinvitae (classified as benign by ClinVar, Invitae, EmvClass; classified as uncertain significance by ClinVar), MutDB , UMD-LSDB (2X classified as neutral), Insight Colon Cancer Gene Variant Database (44X classified as class 1), Zhejiang Colon Cancer Database (7X ), Mismatch Repair Genes Variant Database, databases. The variant was not identified in Cosmic, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant (c.304G>A (p.Glu102Lys)), increasing the likelihood that the p.Leu390Phe variant does not have clinical significance. The variant was identified in control databases in 402(4 homozygous) of 277162 chromosomes at a frequency of 0.00145 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu390 residue is not conserved in mammals and four out of five 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. The variant is located with the DNA mismatch repair protein MutS, core DNA mismatch repair protein, MSH2 functional domains, increasing the likelihood that it may have clinical significance. Functional study of MSH2 on the corresponding yeast allele L402 demonstrated no reduction in steady-state levels of MSH2 and positive interaction with all MSH2 partners (Gammie 2007). The variant was also found co-occurring with pathogenic mutation MLH1 variant c.2157dupT (Wei 2011). However, study by Fan (2005) provides strong molecular epidemiologic, structural, bioinformatic, and functional evidence that MSH2 c.1168C>T (p.Leu390Phe) underlies a newly identified phenotype relevant to young sporadic CRC or GC. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.