ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1331G>T (p.Arg444Leu) (rs557339938)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196756 SCV000254383 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 444 of the MSH2 protein (p.Arg444Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs557339938, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 216342). 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.
Ambry Genetics RCV000214843 SCV000274102 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409612 SCV000489432 uncertain significance Lynch syndrome I 2016-10-11 criteria provided, single submitter clinical testing
Color RCV000214843 SCV000684928 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586261 SCV000696207 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1331G>T (p.Arg444Leu) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured). This variant was found in 2/120114 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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