Submissions for variant NM_000179.3(MSH6):c.3197A>G (p.Tyr1066Cys)

gnomAD frequency: 0.00003  dbSNP: rs372103816

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131293	SCV000186265	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.Y1066C variant (also known as c.3197A>G), located in coding exon 5 of the MSH6 gene, results from an A to G substitution at nucleotide position 3197. The tyrosine at codon 1066 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000234661	SCV000283787	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1066 of the MSH6 protein (p.Tyr1066Cys). This variant is present in population databases (rs372103816, gnomAD 0.005%). This missense change has been observed in individual(s) with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142270). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000131293	SCV000685365	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1066 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913) and an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 5/251354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001560125	SCV001782472	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with glioblastoma, papillary renal carcinoma, and prostate cancer, as well as in health control groups (Lu et al., 2015; Huang et al., 2017; Rosenthal et al., 2018; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 23621914, 28873162, 17531815, 21120944, 30267214, 29625052, 29684080, 26689913)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398768	SCV004121839	uncertain significance	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3197A>G (p.Tyr1066Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251354 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3197A>G has been reported in the literature in individuals affected with cancers including breast, prostate, and pancreatic cancer as well as unaffected controls (Huang_2018, Dorling_2021, Yin_2022). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 29625052, 35171259). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998098	SCV004842783	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1066 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913). This variant has been identified in 5/251354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.