ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.817G>A (p.Val273Ile) (rs530814648)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236426 SCV000293804 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.817G>A at the cDNA level, p.Val273Ile (V273I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). MSH2 c.817G>A was observed, in unknown phase, with MSH2 c.818T>A in an individual with a colorectal tumor demonstrating microsatellite instability and loss of MSH2 protein expression (Pigatto 2004, Sharp 2004). Due to the affected bases being adjacent, if the variants are in cis, this would result in MSH2 Val273Lys, and if in trans, this individual would be compound heterozygous for MSH2 Val273Ile and Val273Glu. However, c.817G>A or another nucleotide substitution resulting in MSH2 Val273Ile alone has not, to our knowledge, been reported in the literature. MSH2 Val273Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector 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 Val273Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000458697 SCV000548233 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 273 of the MSH2 protein (p.Val273Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs530814648, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 246308). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000564711 SCV000676076 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing The p.V273I variant (also known as c.817G>A), located in coding exon 5 of the MSH2 gene, results from a G to A substitution at nucleotide position 817. The valine at codon 273 is replaced by isoleucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000 alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhenbutdeleterious bySIFT in silico analyses.In addition, this alteration is predicted to be benignby MAPP-MMR in silico analyses (Chao E et al. Hum Mutat.2008Jun;29(6):852-60).Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Color Health, Inc RCV000564711 SCV000911234 likely benign Hereditary cancer-predisposing syndrome 2016-08-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356679 SCV001551917 likely benign Endometrial carcinoma no assertion criteria provided clinical testing The MSH2 p.Val273Ile variant was identified in dbSNP (ID: rs530814648) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (2x), and not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 8 of 245604 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), with breakdown of the observations by population include European Non-Finnish in 1 of 111478 chromosomes (freq: 0.000009) and South Asian in 7 of 30496 chromosomes (freq: 0.0002) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian and European Finnish, populations. The variant was also identified by our laboratory in 1 individual with endometrial cancer, co-occurring with a pathogenic MLH1 variant (c.588+1G>C). The p.Val273 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 the variant Ile impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. RNA analysis (RT-PCR and allele specific RT-PCR) of peripheral blood RNA, on a cohort of patients with unclassified variants showed that the MSH2 c.817G>A;c.817T>A/p.Val274Lys was associated with normal RNA expression and splicing (Sharp_2004_ 15300854). 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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