ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1045C>G (p.Pro349Ala) (rs267607939)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128932 SCV000172803 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148635 SCV000190350 uncertain significance Renal cell carcinoma, papillary, 1 2014-06-01 no assertion criteria provided research
Color RCV000128932 SCV000684897 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000764423 SCV000895480 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000588936 SCV000211170 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1045C>G at the cDNA level, p.Pro349Ala (P349A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has been reported in individuals with colorectal, breast, or other cancers, as well as in an Ashkenazi Jewish control subject (Rubio-Del-Campo 2008, Carmi 2014, Cragun 2014, Hansen 2017, Jalkh 2017, Zidan 2017). This variant did not result in 6TG-resistant colony formation, suggesting it does not affect mismatch repair function (Houlleberghs 2016). MSH2 Pro349Ala was observed at an allele frequency of 0.079% (8/10,148) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the Lever domain (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 Pro349Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588936 SCV000696197 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1045C>G (p.Pro349Ala) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the DNA mismatch repair protein MutS, core (InterPro) and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000906 (11/121390 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). However, it is relatively common in the Latino subpopulation at a frequency of 0.000346 (4/11574 in ExAC; 13/34410 in gnomAD). For this subpopulation, the frequency is about 1 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this may be a benign polymorphism. The variant has been cited in publications numerous times with conflicting classifications, including likely pathogenic (Cragun_Clin Genet_2014; LaDuca_GIM_2014), VUS (Hansen_Clin Genet_2017), and non-pathogenic (Houlleberghs_PNAS_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. A functional study was performed in cultured mouse embryonic stem cells that suggested the amino acid residue P349 may be a critical amino acid since the mutants P349L and P349R were defective in MMR function. However, the same study also assayed the variant of interest, P349A, and showed this variant to have intact MMR activity, suggesting this variant specifically has little to no impact on protein function (Houlleberghs_PNAS_2016). Additionally, the variant has been found to co-occur with other pathogenic variants. First, in the INSiGHT database, a male patient diagnosed with colorectal cancer carried the variant along with the MSH2 pathogenic mutation c.223_224delCT (p.Leu75Alafs; classified as pathogenic by INSiGHT curators), and immunohistochemistry showed positive for MLH1, MSH2, and PMS2, with microsatellite instability categorized as MSI-H. Second, a publication that performed whole exome sequencing on Lebanese breast cancer patients (Jalkh_BMC Med Genom_2017) showed the variant in a patient along with the pathogenic BRCA1 mutation c.4327C>T (p.R1443*), which is pathogenic in ClinVar based on 16 submissions, suggesting it is unlikely that the variant contributes to the phenotype in this patient. Taking all information together, this variant is classified as VUS - possibly benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076007 SCV000107018 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524328 SCV000254377 likely benign Hereditary nonpolyposis colon cancer 2017-12-23 criteria provided, single submitter clinical testing
Mendelics RCV000076007 SCV000837825 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000128932 SCV000788028 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-11 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000076007 SCV000887410 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1045C>G has a 99.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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