ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.369A>T (p.Lys123Asn) (rs587782106)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130622 SCV000185498 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000590479 SCV000211339 uncertain significance not provided 2014-07-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.369A>T at the cDNA level, p.Lys123Asn (K123N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys123Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys123Asn occurs at a position that is moderately conserved across species and is located within the PWWP domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Lys123Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590479 SCV000695883 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing Variant summary: This MSH6 variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Lysine (K) with a medium size and polar Asparagine (N). Two in silico tools predict the variant to be benign and two predict deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. It was observed in one CRC patient, however without strong evidence for pathogenicity (Chubb_JCO_2015). Functional studies assessing the functional impact of the variant on the protein were not published at the time of classification. Clinical laboratories via ClinVar classify variant as Uncertain significance (without evidence to independently evaluate). Due to the lack of strong clinical data or functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae RCV000807593 SCV000947655 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 123 of the MSH6 protein (p.Lys123Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 141913). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202268 SCV000257275 uncertain significance not specified no assertion criteria provided research

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