Submissions for variant NM_000179.3(MSH6):c.1127A>G (p.Glu376Gly)

gnomAD frequency: 0.00001  dbSNP: rs764150912

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213418	SCV000274849	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The p.E376G variant (also known as c.1127A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1127. The glutamic acid at codon 376 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available 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	RCV000791357	SCV000551209	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000466266	SCV000837878	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001559019	SCV001781078	uncertain significance	not provided	2023-07-03	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: 22949387, 33471991, 23621914, 33203166, 32664968, 17531815, 21120944)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001559019	SCV002010119	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213418	SCV002535596	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Baylor Genetics	RCV003462454	SCV004197556	uncertain significance	Endometrial carcinoma	2023-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213418	SCV004357573	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 376 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 two individuals affected with breast cancer (PMID: 33471991; DOI: 10.1101/2021.04.15.21255554) and several healthy controls from a breast cancer case-control study (PMID: 33471991). This variant has been identified in 4/282366 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.