Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000656878 | SCV000149413 | uncertain significance | not provided | 2020-06-16 | criteria provided, single submitter | clinical testing | Observed in an individual with a colorectal cancer whose tumor showed microsatellite stability and normal immunohistochemistry and in an individual with a personal and/or family history suggestive of Lynch syndrome (O'Leary 2014, Kraus 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28494185, 25142776, 24728327) |
Invitae | RCV000122981 | SCV000166264 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000492001 | SCV000580410 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-08 | criteria provided, single submitter | clinical testing | The p.R534H variant (also known as c.1601G>A), located in coding exon 10 of the MSH2 gene, results from a G to A substitution at nucleotide position 1601. The arginine at codon 534 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a 68-year-old male patient with colorectal cancer; however this individuals tumor exhibited normal IHC and was MSS (Kraus C et al. Int J Cancer, 2015 Mar;136:E559-68). Another study reported this alteration in a cohort of Chinese esophageal squamous cell carcinoma patients (Ko JM et al. Int J Cancer, 2020 02;146:1042-1051). This variant was reported in 7/60,466 breast cancer cases but also reported in 6/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV000492001 | SCV000684953 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-21 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 534 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Counsyl | RCV000662395 | SCV000784809 | uncertain significance | Lynch syndrome 1 | 2016-12-14 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000121559 | SCV000917715 | uncertain significance | not specified | 2018-07-19 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.1601G>A (p.Arg534His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp domain (IPR007861), which is inserted between the two subdomains of the core domain. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246194 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.3e-05 vs 0.00057), allowing no conclusion about variant significance. c.1601G>A has been reported in the literature in individuals affected with colorectal cancer and in an individual with a positive family history of inherited cancer disorder (Kraus_2015, O'Leary_2014). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.998G>A, p.Cys333Tyr (LOVD)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000656878 | SCV002046197 | uncertain significance | not provided | 2023-08-31 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 25142776 (2015), 28494185 (2017)), breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)), and other unspecified cancers (PMID: 31396961 (2020), 34326862 (2021)). This variant is also reported in unaffected individuals (PMID: 23012121 (2012), 24728327 (2014), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). This variant was determined to be functionally neutral in a mismatch repair assay (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000098 (3/30606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
Sema4, |
RCV000492001 | SCV002534382 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-29 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV000662395 | SCV004018328 | likely benign | Lynch syndrome 1 | 2023-03-21 | 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]. |
Baylor Genetics | RCV000662395 | SCV004196193 | uncertain significance | Lynch syndrome 1 | 2023-10-12 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003997272 | SCV004833904 | uncertain significance | Lynch syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 534 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
ITMI | RCV000121559 | SCV000085753 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
True Health Diagnostics | RCV000492001 | SCV000788030 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-07-17 | no assertion criteria provided | clinical testing |