ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3919A>C (p.Asn1307His) (rs730881808)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160700 SCV000211328 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3919A>C at the cDNA level, p.Asn1307His (N1307H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn1307His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn1307His occurs at a position that is not conserved and is located in the MSH2-binding site and MutS domain I (Kariola 2002, Terui 2013). In silico analyses and splicing models are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Asn1307His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530579 SCV000624943 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 1307 of the MSH6 protein (p.Asn1307His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182649). 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 histidine 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.
Fulgent Genetics,Fulgent Genetics RCV000764436 SCV000895493 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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