ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1830G>C (p.Lys610Asn) (rs201735525)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160672 SCV000211283 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1830G>C at the cDNA level, p.Lys610Asn (K610N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant was observed in an individual with a primary epithelial ovarian cancer (Pal 2012). In addition, the c.1830G>T variant in MSH6 that results in the same amino acid substitution (Lys610Asn) has been reported in at least two families with a history of colorectal cancer (Nilbert 2009) and an in vitro functional assay found this variant had MMR activity similar to wild type (Drost 2012). MSH6 Lys610Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a surface loop of the connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Lys610Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228068 SCV000283731 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 610 of the MSH6 protein (p.Lys610Asn). 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 reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 182627). Experimental studies using a cell-free in vitro assay have shown that this amino acid change does not affect MSH6 mismatch repair activity (PMID: 22102614). 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 RCV000568274 SCV000669953 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000568274 SCV000685231 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-08 criteria provided, single submitter clinical testing

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