Submissions for variant NM_000179.3(MSH6):c.1656T>A (p.His552Gln)

gnomAD frequency: 0.00001  dbSNP: rs745937181

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215555	SCV000278728	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-27	criteria provided, single submitter	clinical testing	The p.H552Q variant (also known as c.1656T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 1656. The histidine at codon 552 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available lower vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000463760	SCV000551177	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215555	SCV000908378	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 552 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26689913). This variant has been identified in 1/250912 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	RCV001753682	SCV002007570	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with ovarian cancer (Lu et al., 2015); This variant is associated with the following publications: (PMID: 17531815, 21120944, 26689913)
Sema4, Sema4	RCV000215555	SCV002535645	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998606	SCV004841835	uncertain significance	Lynch syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 552 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been reported in an individual affected with ovarian cancer (PMID: 26689913). This variant has been identified in 1/250912 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.