ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.818T>C (p.Val273Ala) (rs144288433)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656874 SCV000565184 uncertain significance not provided 2018-12-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.818T>C at the cDNA level, p.Val273Ala (V273A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val273Ala was observed at an allele frequency of 0.05% (5/10306 alleles) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val273Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the Connector domain (L?tzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Val273Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000558255 SCV000625469 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 273 of the MSH2 protein (p.Val273Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs144288433, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 418314). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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 RCV000566262 SCV000669784 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000480961 SCV000712775 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing The p.Val273Ala variant in MSH2 has not been previously reported in individuals with Lynch syndrome but has been identified in 5/10306 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s144288433). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Val273Ala variant is uncertain.
Color RCV000566262 SCV000906665 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing

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