Submissions for variant NM_000251.2(MSH2):c.885C>G (p.Asp295Glu) (rs201334592)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220130	SCV000274132	likely benign	Hereditary cancer-predisposing syndrome	2018-09-29	criteria provided, single submitter	clinical testing	Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Counsyl	RCV000411007	SCV000489642	uncertain significance	Lynch syndrome I	2016-11-02	criteria provided, single submitter	clinical testing
Invitae	RCV000469366	SCV000548203	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glutamic acid at codon 295 of the MSH2 protein (p.Asp295Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs201334592, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 230546). 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	RCV000589679	SCV000567699	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18822302, 21120944, 30212499, 23047549, 29684080)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589679	SCV000696292	uncertain significance	not provided	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.885C>G (p.Asp295Glu) variant located in the DNA mismatch repair protein MutS, connector domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 7/121246 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). A publication, Pal_2012, cites the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories report the variant with conflicting classifications, "likely benign" or "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color Health, Inc	RCV000220130	SCV000903130	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-13	criteria provided, single submitter	clinical testing