Submissions for variant NM_000179.3(MSH6):c.1618C>A (p.Leu540Ile)

dbSNP: rs201996928

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034493	SCV000566410	uncertain significance	not provided	2022-12-10	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: 17531815, 21120944, 22703879)
Color Diagnostics, LLC DBA Color Health	RCV000583196	SCV000690208	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 540 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251312 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.
Invitae	RCV000693805	SCV000821688	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-05-16	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 41589). This variant is present in population databases (rs201996928, ExAC 0.003%). This sequence change replaces leucine with isoleucine at codon 540 of the MSH6 protein (p.Leu540Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine.
Ambry Genetics	RCV000583196	SCV002705359	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing	The p.L540I variant (also known as c.1618C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1618. The leucine at codon 540 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been identified in a cohort of 572 atherosclerosis patients with no clinical history of cancer (Pinard A et al. Hum Mutat, 2016 12;37:1299-1307). This amino acid position is highly 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.
All of Us Research Program, National Institutes of Health	RCV003996170	SCV004839606	uncertain significance	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 540 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251312 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034493	SCV000043356	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.