Submissions for variant NM_000179.3(MSH6):c.3600A>G (p.Ile1200Met)

gnomAD frequency: 0.00002  dbSNP: rs587781482

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129441	SCV000184211	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The p.I1200M variant (also known as c.3600A>G), located in coding exon 7 of the MSH6 gene, results from an A to G substitution at nucleotide position 3600. The isoleucine at codon 1200 is replaced by methionine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/173 patients suspected of having a hereditary tumor syndrome (Henn J et al. Hered Cancer Clin Pract, 2019 Jan;17:5). 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.
Counsyl	RCV000412406	SCV000489165	uncertain significance	Lynch syndrome 5	2016-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000766608	SCV000567957	uncertain significance	not provided	2022-04-25	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 a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26627015, 17531815, 21120944)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478382	SCV000601579	uncertain significance	not specified	2017-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV000539721	SCV000624888	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-30	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 1200 of the MSH6 protein (p.Ile1200Met). This variant is present in population databases (rs587781482, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 141085). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV000129441	SCV001339678	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 1200 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 an individual affected with endometrial cancer (PMID: 33577226). This variant has been identified in 1/251440 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.
Myriad Genetics, Inc.	RCV000412406	SCV004019056	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	RCV003997501	SCV004835098	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 1200 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 an individual affected with endometrial cancer (PMID: 33577226). This variant has been identified in 1/251440 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.