ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1867C>G (p.Pro623Ala) (rs3136334)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128867 SCV000172724 likely benign Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Invitae RCV001082588 SCV000218546 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000034494 SCV000279098 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1867C>G at the cDNA level, p.Pro623Ala (P623A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant was observed in an individual with atherosclerosis, with no specific information about cancer history (Johnston 2012). In an in vivo functional study, this variant was not resistant to a DNA damaging agent suggesting that it is not pathogenic (Houlleberghs 2017). MSH6 Pro623Ala was observed at an allele frequency of 0.13% (32/23,910) in individuals of African ancestry in large population cohorts (Lek 2016). MSH6 Pro623Ala is located in the Connector domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Pro623Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000074692 SCV000296879 uncertain significance Lynch syndrome 2015-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034494 SCV000601519 likely benign not provided 2018-11-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121577 SCV000695798 likely benign not specified 2020-10-15 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1867C>G (p.Pro623Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250462 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1867C>G has been reported in the literature with limited clinical information, predominantly reporting bioinformatic computational predictions that predicted this variant to have a neutral impact (example, Ali_2012, Terui_2013, Niroula_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an oligonucleotide-directed mutagenesis screening assay measuring 6TG resistance in MMR-deficient cells (Houlleberghs_2017). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; uncertain significance, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000662448 SCV000784919 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-02-15 criteria provided, single submitter clinical testing
Color RCV000128867 SCV000902977 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034494 SCV000043357 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121577 SCV000085773 not provided not specified 2013-09-19 no assertion provided reference population

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