ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.383T>G (p.Leu128Arg) (rs730881768)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590606 SCV000211204 uncertain significance not provided 2016-02-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.383T>G at the cDNA level, p.Leu128Arg (L128R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Leu128Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Leu128Arg 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 Leu128Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000197978 SCV000254421 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-04 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 128 of the MSH2 protein (p.Leu128Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. 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: 182576). 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.
Ambry Genetics RCV000217291 SCV000273187 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000515278 SCV000611402 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000217291 SCV000685087 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590606 SCV000696264 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.383T>G (p.Leu128Arg) variant located in the DNA mismatch repair protein MutS-like, N-terminal domain causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories have classified the variant as "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)."
Counsyl RCV000662843 SCV000785703 uncertain significance Lynch syndrome I 2017-11-07 criteria provided, single submitter clinical testing

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