ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2516A>G (p.His839Arg) (rs63750027)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166332 SCV000217118 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing The p.H839R variant (also known as c.2516A>G), located in coding exon 15 of the MSH2 gene, results from an A to G substitution at nucleotide position 2516. The histidine at codon 839 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in a highly conserved ATPase domain of the protein. This alteration has been reported in Chinese and Taiwanese Lynch syndrome families (Yuan Y et al. Jpn. J. Clin. Oncol. 2004 Nov;34:660-6; Wang XL et al. World J. Gastroenterol. 2006 Jul;12:4074-7; Zhu M et al. Oncol Lett. 2013 May;5:1710-1718). However, in one family it was reportedly detected in conjunction with a pathogenic mutation in MLH1 (Tang R et al. Clin. Genet. 2009 Apr;75:334-45). Functional analyses indicate that this alteration moderately reduces mRNA expression, protein viability, and DNA damage response (Arora S et al. Cancer Biol. Ther. 2017 Jul;18:519-533). This alteration has been classified as a variant of uncertain significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46:107-15; available at []). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001085048 SCV000259843 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-10-19 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 I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166332 SCV000911047 likely benign Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000986690 SCV001135761 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
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.

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