Submissions for variant NM_000179.3(MSH6):c.3111C>A (p.Phe1037Leu)

dbSNP: rs587781673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129832	SCV000184648	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-17	criteria provided, single submitter	clinical testing	The p.F1037L variant (also known as c.3111C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 3111. The phenylalanine at codon 1037 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000221076	SCV000279528	uncertain significance	not provided	2015-10-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3111C>A at the cDNA level, p.Phe1037Leu (F1037L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe1037Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Phe1037Leu occurs at a position that is conserved across species and is located in MutS domain III (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Phe1037Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000410297	SCV000489155	uncertain significance	Lynch syndrome 5	2016-08-29	criteria provided, single submitter	clinical testing
Invitae	RCV001298939	SCV001488010	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1037 of the MSH6 protein (p.Phe1037Leu). This variant is not present in population databases (gnomAD no frequency). 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: 141346). 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.
Myriad Genetics, Inc.	RCV000410297	SCV004019065	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997528	SCV004834234	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 1037 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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.