ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3832C>A (p.Pro1278Thr) (rs587782109)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130625 SCV000185501 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000130625 SCV000685448 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000589175 SCV000279324 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3832C>A at the cDNA level, p.Pro1278Thr (P1278T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has been reported in at least one individual with breast cancer (Tung 2015). MSH6 Pro1278Thr was observed at an allele frequency of 0.06% (6/9844) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). MSH6 Pro1278Thr is located in the ATPase domain (Warren 2007, 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 MSH6 Pro1278Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589175 SCV000695891 likely benign not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3832C>A (p.Pro1278Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 14/120906 control chromosomes at a frequency of 0.0001158, predominantly observed in the Latino subpopulation at a frequency of 0.000955 (11/11516). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, one internal specimen has a co-occurrence with a pathogenic frame-shift MSH6 variant, c.2150_2153delTCAG/p.Val717fsX18. Also, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/ uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Invitae RCV000168005 SCV000218656 likely benign Hereditary nonpolyposis colon cancer 2018-01-12 criteria provided, single submitter clinical testing

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