Submissions for variant NM_000179.3(MSH6):c.3098T>A (p.Met1033Lys)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490990	SCV000580322	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-13	criteria provided, single submitter	clinical testing	The p.M1033K variant (also known as c.3098T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 3098. The methionine at codon 1033 is replaced by lysine, an amino acid with few similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data, external communication). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000521749	SCV000618327	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3098T>A at the cDNA level, p.Met1033Lys (M1033K) at the protein level, and results in the change of a Methionine to a Lysine (ATG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met1033Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met1033Lys occurs at a position that is conserved across species and is located within the Lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Met1033Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659893	SCV000781790	likely benign	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865529	SCV002284983	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-05-27	criteria provided, single submitter	clinical testing	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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 428405). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1033 of the MSH6 protein (p.Met1033Lys).

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