Submissions for variant NM_000179.2(MSH6):c.253C>T (p.Pro85Ser) (rs779664343)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204386	SCV000259977	uncertain significance	Hereditary nonpolyposis colon cancer	2019-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 85 of the MSH6 protein (p.Pro85Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. While this variant is present in population databases (rs779664343), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 219868). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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	RCV000482986	SCV000565906	uncertain significance	not provided	2015-03-17	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.253C>T at the cDNA level, p.Pro85Ser (P85S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro85Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro85Ser occurs at a position that is not conserved across species and is not located in a known functional domain (Terui 2013, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Pro85Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575872	SCV000669983	uncertain significance	Hereditary cancer-predisposing syndrome	2017-04-20	criteria provided, single submitter	clinical testing	Insufficient evidence;In silico models in agreement (benign)
Mendelics	RCV000986699	SCV001135779	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2019-05-28	criteria provided, single submitter	clinical testing
Color	RCV000575872	SCV001352501	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-15	criteria provided, single submitter	clinical testing

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