ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.972A>C (p.Lys324Asn) (rs876658610)

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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 RCV000216324 SCV000274094 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000229706 SCV000283863 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 324 of the MSH6 protein (p.Lys324Asn). The lysine residue is weakly 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 undergoing genetic testing for suspected Lynch syndrome (PMID: 25980754). This variant has also been observed in an individual with sebaceous carcinoma of skin (Invitae). However, in that individual, pathogenic alleles were also identified in MSH2, which suggests that this c.972A>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 230518). 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 tolerated, but 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.
GeneDx RCV000483787 SCV000566493 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.972A>C at the cDNA level, p.Lys324Asn (K324N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has been observed in at least one individual with a history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). MSH6 Lys324Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the nuclear localization signals (Gassman 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 Lys324Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000663012 SCV000786027 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-06 criteria provided, single submitter clinical testing
Color RCV000216324 SCV000904762 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing

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