ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.134G>C (p.Gly45Ala)

gnomAD frequency: 0.00001  dbSNP: rs1114167802
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491335 SCV000580380 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-16 criteria provided, single submitter clinical testing The p.G45A variant (also known as c.134G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 134. The glycine at codon 45 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001057562 SCV001222061 benign Hereditary nonpolyposis colorectal neoplasms 2023-12-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328326 SCV001519401 uncertain significance not specified 2021-03-08 criteria provided, single submitter clinical testing Variant summary: MSH6 c.134G>C (p.Gly45Ala) results in a non-conservative amino acid change in 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 3.2e-05 in 31332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.134G>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago RCV001328326 SCV002066876 uncertain significance not specified 2021-02-28 criteria provided, single submitter clinical testing DNA sequence analysis of the MSH6 gene demonstrated a sequence change, c.134G>C, in exon 1 that results in an amino acid change, p.Gly45Ala. This sequence change does not appear to have been previously described in individual with MSH6-related disorders. This sequence change has been described in one African/African American in the gnomAD database (dbSNP rs1114167802). The p.Gly45Ala change affects a poorly conserved amino acid residue of the MSH6 protein. The p.Gly45Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly45Ala change remains unknown at this time.

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