ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3758T>A (p.Val1253Glu) (rs202066386)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656901 SCV000149330 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3758T>A at the cDNA level, p.Val1253Glu (V1253E) at the protein level, and results in the change of a Valine to a Glutamic Acid (GTA>GAA). This variant has been observed in individuals with a lynch syndrome associated cancer and/or polyps, a microsatellite stable colorectal cancer, renal cancer, or breast cancer (Kraus 2015, Lu 2015, Yurgelun 2015, Yehia 2018). MSH6 Val1253Glu was observed at an allele frequency of 0.039% (10/25,788 alleles) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Val1253Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115421 SCV000214209 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000196523 SCV000254320 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 1253 of the MSH6 protein (p.Val1253Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs202066386, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with colorectal, breast, and renal cell cancer (PMID: 25142776, 26689913). ClinVar contains an entry for this variant (Variation ID: 127591). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914, 22949387). However, this prediction has not been confirmed by published functional studies and its 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212688 SCV000539717 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with CRC. MaxMAF is 0.09%. Classified as DM? in HGMD. Classified in ClinVar as VUS by Invitae, Ambry, GeneDx (2 stars). MAF is greater than or equal to disease prevalence
Color RCV000115421 SCV000685442 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115421 SCV000822068 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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