ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2732T>G (p.Leu911Arg) (rs41295182)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524397 SCV000166278 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129717 SCV000184520 likely benign Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing Other data supporting benign classification;Does not segregate with disease in family study (genes with incomplete penetrance)
GeneDx RCV000589745 SCV000211223 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2732T>G at the cDNA level, p.Leu911Arg (L911R) at the protein level, and results in the change of a Leucine to an Arginine (CTA>CGA). This variant has been reported in at least four individuals with colon cancer and one individual with epithelial ovarian cancer (Loader 2002, Barnetson 2008, Pal 2012, Ghazani 2017, Raskin 2017). Loader et al. (2002) concluded that MSH2 Leu911Arg was probably deleterious based on the microsatellite unstable (MSI-H) status observed in one individual?s colon tumor while Barnetson et al. (2008) classified this variant as benign based on computational models and lack of co-segregation. On functional interrogation, this variant did not result in 6TG-resistant colony formation, suggesting it does not affect mismatch repair function (Houlleberghs 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH2 Leu911Arg as a variant of uncertain significance (Thompson 2014). MSH2 Leu911Arg was observed at an allele frequency of 0.01% (16/126,192) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within the helix-turn-helix domain and within the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Leu911Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Pathway Genomics RCV000172810 SCV000223776 uncertain significance Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Color RCV000129717 SCV000292152 likely benign Hereditary cancer-predisposing syndrome 2016-07-29 criteria provided, single submitter clinical testing
Counsyl RCV000172810 SCV000488405 uncertain significance Lynch syndrome I 2016-03-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235177 SCV000539686 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple reports describe as VUS/benign, ExAC: 0.02% (12/64562) European chromosomes
Integrated Genetics/Laboratory Corporation of America RCV000235177 SCV000696255 uncertain significance not specified 2019-09-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2732T>G (p.Leu911Arg) results in a non-conservative amino acid change located in the Helix-turn-helix domain (amino acids 856-934) (Houlleberghs_2016). 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 6.8e-05 in 249982 control chromosomes (gnomAD, exomes dataset), predominantly within Non-Finnish Europeans (at a frequency of 0.00014), where the variant was found in the Swedish subpopulation at a frequency of 0.00031 (8/26028). This frequency is somewhat lower than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), though the variant still might represent a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2732T>G has been reported in the literature in individuals affected with colon cancer (e.g. Loader_2002, Barnetson_2008, Ghazani_2017, Raskin_2017) and in a patient with ovarian cancer (Pal_2012), but was also found in unaffected individuals (Karageorgos_2015, Arora_2015). However, one of these studies reported the variant to not segregate with disease in a family (Barnetson_2008), and in another report the associated microsatellite instable colon tumor showed the absence of the MLH1/PMS2 proteins (Raskin_2017). These data therefore do not allow unequivocal conclusions about variant significance. At least one publication reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant on MMR activity in mouse embryonic stem cells (Houlleberghs_2016). Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (6x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000589745 SCV000806035 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000760996 SCV000890911 uncertain significance Embryonal rhabdomyosarcoma; Ectomesenchymoma 2016-03-03 no assertion criteria provided clinical testing

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