ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1963G>A (p.Val655Ile) (rs549467183)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217714 SCV000273748 likely benign Hereditary cancer-predisposing syndrome 2017-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Color RCV000217714 SCV000903533 benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Counsyl RCV000662941 SCV000785899 likely benign Lynch syndrome I 2018-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000115514 SCV000149423 uncertain significance not provided 2017-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1963G>A at the cDNA level, p.Val655Ile (V655I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has been observed in at least one individual with early-onset colon cancer (Shirts 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely not pathogenic, based on unpublished data (Thompson 2014). MSH2 Val655Ile was observed at an allele frequency of 0.104% (12/11572) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val655Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the APTase domain and the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Val655Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780441 SCV000917691 uncertain significance not specified 2017-09-15 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1963G>A (p.Val655Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 35/276926 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000814 (28/34410). This frequency is about 1.4 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in a patient with colon cancer without strong evidence for causality (Shirts_2016), and in a breast cancer patient who carried a pathogenic BRCA1 mutation which explains the patients' disease (Tung_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance or likley benign. Taken together, this variant is classified as a VUS - possibly benign variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000662941 SCV000807673 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA
Invitae RCV000524368 SCV000284129 likely benign Hereditary nonpolyposis colon cancer 2017-11-06 criteria provided, single submitter clinical testing
PreventionGenetics RCV000115514 SCV000806017 likely benign not provided 2017-05-10 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210146 SCV000266196 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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