ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.124C>T (p.Pro42Ser) (rs34014629)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131942 SCV000186998 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000524105 SCV000253087 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-30 criteria provided, single submitter clinical testing
Counsyl RCV000410444 SCV000488256 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-02-09 criteria provided, single submitter clinical testing
GeneDx RCV001719808 SCV000513671 likely benign not provided 2020-11-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25980754, 21153778, 23621914, 22290698, 15872200, 22949387, 26437257, 23581296, 28874130, 19593635, 31647837)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000422207 SCV000695777 likely benign not specified 2021-05-24 criteria provided, single submitter clinical testing Variant summary: MSH6 c.124C>T (p.Pro42Ser) results in a non-conservative amino acid change located in the PWWP domain (IPR000313) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function, and two independent tools developed and reported in the literature predict the variant to be neutral (Terui_2013, Ali_2012). The variant allele was found at a frequency of 0.00011 in 227574 control chromosomes, predominantly at a frequency of 0.0019 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 13 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.124C>T, has been reported in the literature in individuals affected with colorectal cancer or with suspected Lynch Syndrome (example, Hampel_2005, Yurgelun_2015, da Silva_2015, Rossi_ 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000131942 SCV000902798 likely benign Hereditary cancer-predisposing syndrome 2015-09-30 criteria provided, single submitter clinical testing
Mendelics RCV000410444 SCV001135775 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354476 SCV001549103 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Pro42Ser variant was identified in 3 of 3168 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome (Hampel 2005, Yurgelun 2015, Carneiro da Silva 2015 26437257). The variant was identified in dbSNP (rs34014629) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and 2 other submitters; and as uncertain significance by InSiGHT and Counsyl). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 40 of 258,896 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 39 of 21,150 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant) and Latino in 1 of 34,080 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Pro42 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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