ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.107C>T (p.Ala36Val) (rs61756469)

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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 RCV000128922 SCV000172791 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing The p.A36V variant (also known as c.107C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 107. The alanine at codon 36 is replaced by valine, an amino acid with similar properties. This alteration has been reported in two family members affected with non-medullary thyroid cancer (Yu Y et al. Sci Rep. 2015 Nov;5:16129). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. <span style="font-family:arial,sans-serif">Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000220784 SCV000279090 likely benign not provided 2021-04-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26530882, 23621914, 29616133, 30132833)
Invitae RCV000226897 SCV000283699 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000412094 SCV000488415 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-03-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128922 SCV000685162 likely benign Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Mendelics RCV000708850 SCV000837862 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220784 SCV000889452 uncertain significance not provided 2019-01-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780475 SCV000917752 likely benign not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. An algorithm developed specifically to ascertain variants in MSH6 gene suggest that this missense change has no impact on MSH6 function (Terui_2013). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.35 fold above 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 East Asian origin. The c.107C>T has been reported in the literature in two family members affected with familial non-medullary thyroid cancer without reported personal or family history of Lynch Syndrome; both individuals also carried in-frame variant in GNAS gene (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000412094 SCV001135773 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356921 SCV001552213 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 p.Ala36Val variant was identified in the literature however the frequency of this variant in an affected population was not provided (Terui_2013_23621914, Yu_2015_26530882). The variant was also identified in the following databases: dbSNP (ID: rs61756469) as “With Uncertain significance allele”, ClinVar (5x as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Geomics) and Clinvitae (4x as uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database and Insight Hereditary Tumors Database. The variant was identified in control databases in 36 of 263104 chromosomes at a frequency of 0.00014 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 5 of 117454 chromosomes (freq: 0.000043), Ashkenazi Jewish in 1 of 9824 chromosomes (freq: 0.0001), East Asian in 14 of 18328 chromosomes (freq: 0.00076), European Finnish in 8 of 25266 chromosomes (freq: 0.0003), and South Asian in 8 of 30212 chromosomes (freq: 0.00026); while the variant was not observed in the African, “Other” and Latino, populations. The p.Ala36 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.

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