ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3245C>T (p.Pro1082Leu) (rs191109849)

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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 RCV000115409 SCV000185751 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115409 SCV000537600 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000656898 SCV000149318 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3245C>T at the cDNA level, p.Pro1082Leu (P1082L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was reported in an individual with suspected Lynch syndrome whose tumor showed loss of MSH6 protein expression, in a cohort of BRCA1/2 negative individuals with early-onset breast cancer, and in an individual with endometrial stromal sarcoma (Zahary 2014, Maxwell 2015, Ballinger 2016). This variant was observed at an allele frequency of 0.15% (52/34,400) in individuals of Latino ancestry in large population cohorts (Lek 2016). MSH6 Pro1082Leu 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 Pro1082Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121583 SCV000085779 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000121583 SCV000919724 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3245C>T (p.Pro1082Leu) variant involves the alteration of a conserved nucleotide located in the DNA mismatch repair protein MutS core domain (InterPro). 3/5 in silico tools predict a damaging outcome for this variant, however, multiple publications predict this variant is neutral using computational algorithms. This variant was found in 86/278452 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.001512 (52/34400). This frequency is about 11 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. This variant has been reported in multiple patients with different types of cancer, including LS, breast cancer, or colon cancer. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance and one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as VUS-possibly benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074824 SCV000108035 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524160 SCV000254309 likely benign Hereditary nonpolyposis colon cancer 2018-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000074824 SCV000837911 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000656898 SCV000805884 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing

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