Submissions for variant NM_000179.3(MSH6):c.1666T>C (p.Tyr556His)

dbSNP: rs1060502895

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463114	SCV000551097	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-12-07	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410424). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 556 of the MSH6 protein (p.Tyr556His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.
Color Diagnostics, LLC DBA Color Health	RCV001186462	SCV001352879	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 556 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥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 not been identified 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.
Ambry Genetics	RCV001186462	SCV002706089	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.Y556H variant (also known as c.1666T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1666. The tyrosine at codon 556 is replaced by histidine, an amino acid with similar properties. This variant was detected in 1/593 CRC patients and 0/48 healthy controls (Berginc G et al. Fam. Cancer, 2009 Jun;8:421-9). In another study, this alteration was classified as not pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Hum. Mutat., 2013 Jan;34:200-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration has also been predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325202	SCV004031216	uncertain significance	Lynch syndrome 5	2023-06-28	criteria provided, single submitter	clinical testing	The MSH6 c.1666T>C (p.Tyr556His) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.