ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2785C>T (p.Arg929Ter) (rs551060742)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000487485 SCV000574719 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000487485 SCV000685073 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000410460 SCV000489175 uncertain significance Lynch syndrome I 2016-08-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236645 SCV000592556 uncertain significance not specified 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000586820 SCV000292728 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2785C>T at the cDNA level and p.Arg929Ter (R929X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). Pinto et al. (2016) reported MSH2 Arg929Ter to co-occur with a nonsense MSH6 variant in eight unrelated Portuguese Lynch syndrome families, suggesting the two variants were present on the same chromosome (in cis). MSH2 and MSH6 are clustered on chromosome 2. Tumor immunohistochemistry (IHC) revealed normal MSH2 expression in 5/8 cases and absence of MSH6 protein in 7/7 cases with interpretable data. In a ninth family in this report, MSH2 Arg929Ter was observed without the MSH6 truncating variant in an individual with colorectal cancer and no family history of cancer. This variant has also been reported in two individuals with colorectal cancer, co-occurring with a pathogenic MSH2 founder pathogenic variant in one individual (Parc 2003, Valentin 2011). Lastly, this variant has been observed in individuals with breast and/or ovarian cancer (Pennington 2014, Lin 2016, Sun 2017). This variant is in the last exon of the gene and is expected to cause loss of the last 6 amino acids. However, due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated RNA decay and could therefore encode a truncated protein that retains some normal function. MSH2 Arg929Ter was observed at an allele frequency of 0.10% (19/18,812) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Based on currently available evidence, we consider MSH2 Arg929Ter to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586820 SCV000696256 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2785C>T (p.Arg929X) variant results in a premature termination codon in the final 3 part of the gene, encoding a protein that is 6 AA shorter and without interruption of any known functional domain (Pinto_JHG_2016). One in silico tool predicts a damaging outcome for this variant. This variant was found in 9/114040 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001065 (9/8454) in ExAC. This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this might be a benign polymorphism found primarily in the populations of East Asian origin. Also, this variant was reported in multiple studies in patients with LS as co-occurring with pathogenic variants MSH2, c. 942+3A>T and MSH6 c.1030C>T, p.Gln344Ter (Valentin_Fam Cancer_2011, Pinto_JHG_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, with one classifying it as likely benign. MSH2 and MSH6 are both on chromosome 2 and it can be inferred the two mutations are in cis and transmitted together (Pinto_JHG_2016), however this variant could confer an increased risk for disease and/or contribute to the mechanism of disease when another pathogenic mutation is present. Considering these conflicting evidence, this variant is classified as a VUS until functional data becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000708848 SCV000107577 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Nonsense variant after codon 888 in MSH2 = VUS
Invitae RCV000076547 SCV000166279 benign Hereditary nonpolyposis colon cancer 2017-12-09 criteria provided, single submitter clinical testing
Mendelics RCV000708848 SCV000837860 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236645 SCV000601470 likely benign not specified 2017-06-14 criteria provided, single submitter clinical testing

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