Submissions for variant NM_000179.3(MSH6):c.16A>C (p.Thr6Pro)

gnomAD frequency: 0.00005  dbSNP: rs200944853

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490967	SCV000580276	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-20	criteria provided, single submitter	clinical testing	The p.T6P variant (also known as c.16A>C), located in coding exon 1 of the MSH6 gene, results from an A to C substitution at nucleotide position 16. The threonine at codon 6 is replaced by proline, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with high grade glioma (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000549468	SCV000624680	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759128	SCV000888248	uncertain significance	not provided	2018-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000490967	SCV001346620	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 6 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with glioma (PMID: 26580448) and unspecified cancer (PMID: 29684080). This variant has been identified in 2/276232 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	RCV000759128	SCV001787562	uncertain significance	not provided	2023-02-01	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; This variant is associated with the following publications: (PMID: 10612827, 29684080, 26580448, 12019211, 21120944)
Baylor Genetics	RCV003464056	SCV004195631	uncertain significance	Endometrial carcinoma	2023-08-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535548	SCV004717661	uncertain significance	MSH6-related disorder	2024-02-06	criteria provided, single submitter	clinical testing	The MSH6 c.16A>C variant is predicted to result in the amino acid substitution p.Thr6Pro. This variant has been reported in an individual with high grade glioma (Zhang et al. 2015. PubMed ID: 26580448, Table S4a, Case SJHGG073) and in at least one individual with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (Yehia et al. 2018. PubMed ID: 29684080, Table S9). This variant is reported in 0.0084% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/428380/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003459	SCV004832165	uncertain significance	Lynch syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 6 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/276232 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.