Submissions for variant NM_000179.3(MSH6):c.1786T>A (p.Phe596Ile)

dbSNP: rs587779918

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115383	SCV000149292	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20028993, 23047549, 17531815, 21120944)
Invitae	RCV000233835	SCV000283727	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409692	SCV000489120	uncertain significance	Lynch syndrome 5	2016-08-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562745	SCV000669912	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.F596I variant (also known as c.1786T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 1786. The phenylalanine at codon 596 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected at least once in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al, 2012 Nov;107:1783-90). This alteration was also seen in conjunction with a second MSH6 alteration in one family from Scotland with Lynch syndrome (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201). 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.
Color Diagnostics, LLC DBA Color Health	RCV000562745	SCV000911937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 596 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 affected with Lynch syndrome-associated cancers (PMID: 20028993, 23047549). This variant has also been identified in 1/250306 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800402	SCV002046478	uncertain significance	not specified	2020-11-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409692	SCV004019048	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
All of Us Research Program, National Institutes of Health	RCV003997237	SCV004840107	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 596 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 affected with Lynch syndrome-associated cancers (PMID: 20028993, 23047549). This variant has also been identified in 1/250306 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.