ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Invitae RCV000656898 SCV000254309 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Color RCV000115409 SCV000537600 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656898 SCV000805884 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing
Mendelics RCV000074824 SCV000837911 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121583 SCV000919724 likely benign not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3245C>T (p.Pro1082Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. At-least two in-silico studies have reported this variant to have no or neutral impact on MSH6 protein function (Ali_2012, Terui_2013). The variant allele was found at a frequency of 0.00034 in 252712 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 9.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3245C>T has been reported in the literature in individuals affected with suspected Lynch syndrome, breast cancer, colon cancer or prostate cancer (Zahary_2014, Maxwell_2015, Kalady_2015, Isaaccon Velho_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with two other pathogenic variants have been reported in one specimen tested at our laboratory (BRCA1 c.45delT, p.Asn16MetfsX7; BARD1 c.55G>T, p.Glu19X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories (VUS=5 and likely benign = 1) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. We have previously classified this variant as VUS-possibly benign citing overlapping publications (2018). Based on the updated evidence outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656898 SCV001134425 likely benign not provided 2019-02-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656898 SCV001152300 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
ITMI RCV000121583 SCV000085779 not provided not specified 2013-09-19 no assertion provided reference population

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