ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.11A>T (p.Gln4Leu) (rs754562075)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219790 SCV000276465 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000235807 SCV000293611 uncertain significance not provided 2015-11-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.11A>T at the cDNA level, p.Gln4Leu (Q4L) at the protein level, and results in the change of a Glutamine to a Leucine (CAG>CTG) in exon 1. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln4Leu 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 Glutamine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gln4Leu occurs at a position that is conserved across species and is located in the mismatch binding domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gln4Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473744 SCV000548321 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with leucine at codon 4 of the MSH2 protein (p.Gln4Leu). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is present in population databases (rs754562075, ExAC 0.005%) but has not been reported in the literature in individuals with an MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 232346). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). The leucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663256 SCV000786483 uncertain significance Lynch syndrome I 2018-05-08 criteria provided, single submitter clinical testing
Color RCV000219790 SCV001344419 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing

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