Submissions for variant NM_000251.2(MSH2):c.2407A>G (p.Thr803Ala) (rs63751168)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000543029	SCV000625378	uncertain significance	Hereditary nonpolyposis colon cancer	2017-07-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with alanine at codon 803 of the MSH2 protein (p.Thr803Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with gastric cancer, however, the germline nature of this variant was not ascertained (PMID: 21528233). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In addition, an algorithm developed specifically for the MSH2 gene classifies this missense change as a variant of uncertain significance (PMID: 18383312). However, 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.
Integrated Genetics/Laboratory Corporation of America	RCV000588000	SCV000696248	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.2407A>G (p.Thr803Ala) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121386 control chromosomes and has been reported in the literature, without strong evidence for causality. The variant has not been reported in databases, nor evaluated via any funcitonal studies. Therefore, this variant is classified as VUS until additional evidence becomes available.

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