ClinVar Miner

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

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Total submissions: 11
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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 2020-11-25 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 Health, Inc 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034556 SCV001502303 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356651 SCV001551878 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Glu809Lys variant was identified in 2 of 304 proband chromosomes (frequency: 0.007) from individuals or families with Lynch syndrome and was present in 4 of 600 control chromosomes (frequency: 0.007) from healthy individuals (Liu 2014, Tang 2009). The variant was also identified in dbSNP (ID: rs202145681) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by three submitters; as uncertain significance by one submitter), and in UMD-LSDB (1x as unclassified variant). In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.583G>T, p.Gly195X), increasing the likelihood that the p.Glu809Lys variant does not have clinical significance. The variant was identified in control databases in 77 of 277132 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 77 of 18870 chromosomes (freq: 0.004), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Glu809 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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