Submissions for variant NM_000251.3(MSH2):c.2516A>G (p.His839Arg)

gnomAD frequency: 0.00004  dbSNP: rs63750027

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166332	SCV000217118	benign	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV001085048	SCV000259843	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076492	SCV000266197	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000486446	SCV000565203	uncertain significance	not provided	2018-12-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2516A>G at the cDNA level, p.His839Arg (H839R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). MSH2 His839Arg was observed in two unrelated individuals, each with a personal and family history of colorectal cancer, one of whom also harbored a pathogenic MLH1 variant, and was also identified in five cancer-free relatives of the second individual (Yuan 2004, Tang 2009). This variant has also been observed in a breast cancer patient (Shirts 2016). In vitro functional studies demonstrated reduced mRNA expression, protein expression, and cell viability, but no significant defects in DNA damage signaling responses conferred by this variant (Arora 2017). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance (Thompson 2014). MSH2 His839Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH2 His839Arg is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 His839Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000765673	SCV000897015	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166332	SCV000911047	likely benign	Hereditary cancer-predisposing syndrome	2017-01-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000986690	SCV001135761	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153356	SCV003843841	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525868	SCV005040101	likely benign	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.2516A>G (p.Tyr839Cys) results in a non-conservative amino acid change located in the Glycine dehydrogenase, C-terminal domain (IPR049316) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2516A>G has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 2136734). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354097	SCV001548627	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.His839Arg variant was identified in 3 of 428 proband chromosomes (frequency: 0.007) from individuals or families with Lynch syndrome and was not identified in 400 control chromosomes from healthy individuals (Tang 2009, Wang 2006, Yuan 2004). The variant was also identified in dbSNP (ID: rs63750027) as "With Uncertain significance allele" and in ClinVar (classified as likely benign by Invitae; and as uncertain significance by InSiGHT, Ambry Genetics, GeneDx and one other submitter). The variant was not identified in UMD-LSDB. The variant was identified in 8 of 277214 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.0002) and East Asian in 7 of 18866 chromosomes (freq: 0.0004), but was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. Functional and structural analysis of the variant showed reduced protein expression as well as altered RNA structure and MutSα dimerization (Arora 2017). The p.His839 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.