Description
Variant summary: MSH6 c.2281A>G (p.Arg761Gly) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1614172 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.2281A>G has also been reported in the literature in individuals affected with polyps and/or tumors belonging to Lynch syndrome tumor spectrum (e.g. Rey_2017, Ricker_2017, Martin-Morales_2018), in individuals affected with other tumor phenotypes (e.g. Yehia_2018, Dorling_2021, Castillo-Guardioloa_2022, Sahin_2022), as well as in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23621914, 28502729, 28640387, 30256826, 29684080, 33471991, 35089076, 35245693). ClinVar contains an entry for this variant (Variation ID: 140836). Based on the evidence outlined above, the variant was classified as likely benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
