ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1875C>T (p.Ser625=) (rs63749886)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074695 SCV000107899 likely benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.001-0.049 (0.029)
Ambry Genetics RCV000162760 SCV000213237 likely benign Hereditary cancer-predisposing syndrome 2015-01-22 criteria provided, single submitter clinical testing
Invitae RCV001084121 SCV000252626 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000074695 SCV000430965 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504553 SCV000592593 benign not specified 2015-03-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000504553 SCV000601522 likely benign not specified 2017-05-02 criteria provided, single submitter clinical testing
Color RCV000162760 SCV000690231 benign Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Counsyl RCV000663035 SCV000786072 likely benign Hereditary nonpolyposis colorectal cancer type 5 2018-02-23 criteria provided, single submitter clinical testing
Mendelics RCV000074695 SCV000837890 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759847 SCV000889463 likely benign not provided 2017-05-02 criteria provided, single submitter clinical testing
Mendelics RCV000663035 SCV001135812 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000504553 SCV001361761 likely benign not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1875C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 250376 control chromosomes in the gnomAD database. This frequency is approximately the same as the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.00014). However, in some subpopulations the variant was found at higher allele frequencies (e.g. 0.0006 in the Finnish, and 0.00017 in the Latino subpopulation), suggesting a benign role for the variant. c.1875C>T has been reported in the literature in individuals affected with breast- and ovarian cancer (Vahteristo 2005, Pal 2012). These reports however do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A co-occurrence with another pathogenic variant has been reported (MSH6 c.3920dup (p.Asn1307LysfsX12) in the UMD database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (1x), likely benign (4x) and benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.

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