ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3758T>C (p.Val1253Ala) (rs202066386)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656902 SCV000211326 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3758T>C at the cDNA level, p.Val1253Ala (V1253A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has been identified in at least one individual with a personal and family history of colon cancer, one individual with a history of Lynch syndrome-associated cancer and/or polyps (Chubb 2015, Yurgelun 2015), as well as in 1/331 healthy European individuals undergoing whole genome sequencing; however, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant (Bodian 2014). MSH6 Val1253Ala was also observed in an individual with a history of breast and pancreatic cancer (Dudley 2018). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val1253Ala is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Val1253Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160698 SCV000214443 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000206271 SCV000260238 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1253 of the MSH6 protein (p.Val1253Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs202066386, ExAC 0.003%). This variant has been reported in an individual with a personal and family history of colon cancer (PMID: 25559809), and an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 134856). 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 disruptive, 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.
Counsyl RCV000411602 SCV000489110 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-22 criteria provided, single submitter clinical testing
Color RCV000160698 SCV000690394 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121589 SCV000917739 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3758T>C (p.Val1253Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/278234 control chromosomes at a frequency of 0.0000216, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). This variant has been reported in multiple patients without strong evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
ITMI RCV000121589 SCV000085785 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000160698 SCV000788053 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing

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