ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2801C>A (p.Thr934Lys) (rs587779969)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234169 SCV000284162 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 934 of the MSH2 protein (p.Thr934Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs587779969, ExAC 0.005%). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 237394). 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. 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 RCV000767184 SCV000292861 uncertain significance not provided 2015-12-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2801C>A at the cDNA level, p.Thr934Lys (T934K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). This variant was observed in 1/1893 unselected ovarian cancer patients (Pal 2012). MSH2 Thr934Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Thr934Lys occurs at a position that is not conserved and is located in the MSH6 and MSH3 interaction region (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Thr934Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235791 SCV000592557 uncertain significance not specified 2014-08-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564878 SCV000673905 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000662845 SCV000785706 uncertain significance Lynch syndrome I 2017-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235791 SCV000919703 uncertain significance not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2801C>A (p.Thr934Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 274042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2801C>A has been reported in the literature in individuals affected with ovarian cancer (Pal_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000662845 SCV001302502 uncertain significance Lynch syndrome I 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV000564878 SCV001352317 likely benign Hereditary cancer-predisposing syndrome 2016-06-17 criteria provided, single submitter clinical testing

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