Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000234169 | SCV000284162 | benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-18 | criteria provided, single submitter | clinical testing | |
Gene |
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. |
Ambry Genetics | RCV000564878 | SCV000673905 | likely benign | Hereditary cancer-predisposing syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Counsyl | RCV000662845 | SCV000785706 | uncertain significance | Lynch syndrome 1 | 2017-11-08 | criteria provided, single submitter | clinical testing | |
Women's Health and 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 Laboratory Services, |
RCV000662845 | SCV001302502 | uncertain significance | Lynch syndrome 1 | 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 Diagnostics, |
RCV000564878 | SCV001352317 | likely benign | Hereditary cancer-predisposing syndrome | 2016-06-17 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000767184 | SCV002774622 | uncertain significance | not provided | 2021-07-20 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000662845 | SCV004018218 | likely benign | Lynch syndrome 1 | 2023-03-16 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. |
Department of Pathology and Laboratory Medicine, |
RCV001353614 | SCV000592557 | uncertain significance | Lynch syndrome | no assertion criteria provided | clinical testing | The MSH2 p.Thr934Lys variant was not identified in the literature, nor has it been previous identified by our laboratory. The variant was identified in UMD (1X as an unclassified variant). The p.Thr934 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; in addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. This substitution occurs in the last codon before the translational stop codon. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. |