ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.820A>G (p.Ile274Val) (rs371944271)

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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 RCV000167160 SCV000217991 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000198455 SCV000254430 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 274 of the MSH2 protein (p.Ile274Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs371944271, ExAC 0.04%). This variant has been observed in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 187433). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000587804 SCV000292620 uncertain significance not provided 2018-01-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.820A>G at the cDNA level, p.Ile274Val (I274V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been observed in least one individual with epithelial ovarian cancer (Pal 2012). MSH2 Ile274Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ile274Val is located within the connector domain (Lutzen 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 Ile274Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587804 SCV000696288 uncertain significance not provided 2016-04-21 criteria provided, single submitter clinical testing Variant summary: The c.820A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 4/5 in-silico tools predict this variant to be benign. 2/5 splice-tools in Alamut predict that this variant may create a novel 3' splicing acceptor site as well as a novel ESE site for SRp40. However, these predictions have yet to be confirmed by experimental studies. This variant is found in 4/121156 control chromosomes at a frequency of 0.000033, which does not exceed the maximal expected frequency of a pathogenic allele (0.0005683). This variant has been reported in one patient with ovarian cancer without clear evidence supporting pathogenicity (Pal_2012). In addition, several clinical laboratories/reputable databases classified this variant as VUS. Due to the absence of clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000663108 SCV000786225 uncertain significance Lynch syndrome I 2018-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587804 SCV001134376 uncertain significance not provided 2018-11-25 criteria provided, single submitter clinical testing
Color RCV000167160 SCV001343432 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001248898 SCV001422581 uncertain significance not specified 2020-01-22 no assertion criteria provided curation The p.Ile274Val variant in MSH2 has been reported in 1 individual with primary epithelial ovarian cancer (PMID: 23047549), and as been identified in 0.02407% (6/24926) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371944271). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as a VUS by 5 submitters (Variation ID: 187433). The Isoleucine (Ile) at position 274 is not highly conserved in mammals and evolutionary distant species, and 12 species (Shrew, Tetraodon, Fugu, Nile tilapia, Burton's mouthbreeder, Princess of Burundi, Zebra mbuna, Pundamilia nyererei, Medaka, Stickleback, Atlantic cod, and Lamprey) carry a Valine (Val), raising the possibility that this change at this position may be tolerated. However, other computational prediction tools do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Ile274Met, has been reported as a VUS in association with disease in ClinVar (Variation ID: 472815). In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: None (Richards 2015).

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