Submissions for variant NM_000251.3(MSH2):c.2425G>A (p.Glu809Lys)

gnomAD frequency: 0.00013  dbSNP: rs202145681

Total submissions: 14

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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001080801	SCV000260613	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	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 Diagnostics, LLC DBA Color Health	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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121564	SCV002046323	benign	not specified	2020-10-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129519	SCV002534475	likely benign	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003914905	SCV004733338	likely benign	MSH2-related condition	2020-01-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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 1		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.
GenomeConnect, ClinGen	RCV001787035	SCV002029151	not provided	Hereditary nonpolyposis colon cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-15-2018 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.