ClinVar Miner

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

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Total submissions: 6
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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 In silico models in agreement (benign);Co-occurence with mutation in same gene (phase unknown)
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 2020-01-12 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 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.885C>G at the cDNA level, p.Asp295Glu (D295E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has been reported in at least one individual with ovarian cancer (Pal 2012). MSH2 Asp295Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MSH2 Asp295Glu occurs at a position that is conserved across species and is located in the connector 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 Asp295Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America 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 RCV000220130 SCV000903130 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing

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