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	2017-06-08	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae	RCV000229706	SCV000283863	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-28	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	2018-06-03	criteria provided, single submitter	clinical testing

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