Submissions for variant NM_000179.3(MSH6):c.2906A>T (p.Tyr969Phe)

gnomAD frequency: 0.00006  dbSNP: rs63749919

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129763	SCV000184570	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.Y969F variant (also known as c.2906A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 2906. The tyrosine at codon 969 is replaced by phenylalanine, an amino acid with highly similar properties. 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). Another missense variant at this same codon, p.Y969C, has been reported in multiple families with Lynch syndrome with tumors exhibiting a loss of MSH6 staining on IHC (Suchy J et al. Clin. Genet. 2006; 70:68-70; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). 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	RCV000204094	SCV000259463	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000410024	SCV000488897	uncertain significance	Lynch syndrome 5	2016-07-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129763	SCV001348348	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 969 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 an individual affected by skin melanoma (PMID: 29684080). This variant has been identified in 4/274208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.2906A>G (p.Tyr969Cys) and c.2905T>C (p.Tyr969His), are considered to be likely disease-causing (ClinVar variation ID: 234622, 433916), suggesting that Tyr at this position is important for protein function. 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	RCV002288628	SCV002578525	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Myriad Genetics, Inc.	RCV000410024	SCV004019064	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003997522	SCV004838967	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 969 of the MSH6 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. A different variant affecting the same codon, c.2906A>G (p.Tyr969Cys), is considered to be likely disease-causing (ClinVar variation ID: 234622), suggesting that Tyr or similar amino acid at this position is important for protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/274208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.