Submissions for variant NM_000251.2(MSH2):c.55T>G (p.Phe19Val) (rs141711342)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486701	SCV000566408	uncertain significance	not provided	2015-04-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.55T>G at the cDNA level, p.Phe19Val (F19V) at the protein level, and results in the change of a Phenylalanine to a Valine (TTC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Phe19Val 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 Phenylalanine and Valine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Phe19Val occurs at a position that is conserved across species and is located in the mismatch binding domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Phe19Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000695062	SCV000823539	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2018-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with valine at codon 19 of the MSH2 protein (p.Phe19Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 418959). 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, 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.