Submissions for variant NM_000179.3(MSH6):c.2175C>G (p.Ile725Met)

gnomAD frequency: 0.00001  dbSNP: rs63750304

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410569	SCV000488837	uncertain significance	Lynch syndrome 5	2016-06-29	criteria provided, single submitter	clinical testing
Invitae	RCV000556059	SCV000624731	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 725 of the MSH6 protein (p.Ile725Met). This variant is present in population databases (rs63750304, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 11709755). ClinVar contains an entry for this variant (Variation ID: 89257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. 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.
Ambry Genetics	RCV000565677	SCV000662560	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	clinical testing	The p.I725M variant (also known as c.2175C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2175. The isoleucine at codon 725 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in an individual diagnosed with colon cancer at 36, whose tumor showed presence of the MLH1, MSH2, and MSH6 proteins on immunohistochemistry, low microsatellite instability, and absence of the BRAF V600E mutation (Berends MJ et al. Am. J. Hum. Genet., 2002 Jan;70:26-37; Domingo E et al. Oncogene, 2005 Jun;24:3995-8). This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000565677	SCV000908260	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 725 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 colorectal cancer (PMID: 11709755, 16636019). Tumors from one of these individuals showed low microsatellite instability, as well as normal expression of MLH1, MSH2 and MSH6 proteins via immunohistochemistry analysis (PMID: 11709755). This variant has been identified in 4/250950 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149718	SCV003837643	uncertain significance	Breast and/or ovarian cancer	2021-06-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410569	SCV004019070	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	RCV003997071	SCV004836107	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 725 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 colorectal cancer (PMID: 11709755, 16636019). Tumors from one of these individuals showed low microsatellite instability, as well as normal expression of MLH1, MSH2 and MSH6 proteins via immunohistochemistry analysis (PMID: 11709755). This variant has been identified in 4/250950 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.