Submissions for variant NM_000179.3(MSH6):c.3565A>G (p.Thr1189Ala)

gnomAD frequency: 0.00001  dbSNP: rs753778809

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218856	SCV000275546	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The p.T1189A variant (also known as c.3565A>G), located in coding exon 7 of the MSH6 gene, results from an A to G substitution at nucleotide position 3565. The threonine at codon 1189 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly 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.
GeneDx	RCV000482279	SCV000571476	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21120944, 17531815)
Invitae	RCV000558107	SCV000624884	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1189 of the MSH6 protein (p.Thr1189Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 231639). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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	RCV000218856	SCV001341890	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1189 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 7/245816 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798716	SCV002042054	uncertain significance	Breast and/or ovarian cancer	2019-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462471	SCV004195710	uncertain significance	Endometrial carcinoma	2023-06-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493521	SCV004243102	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997917	SCV004835094	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1189 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual screened for hereditary breast/ovarian cancer (PMID: 34359559). This variant has been identified in 7/245816 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.