Submissions for variant NM_000179.3(MSH6):c.3679A>T (p.Ile1227Leu)

gnomAD frequency: 0.00001  dbSNP: rs587779282

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217680	SCV000279524	uncertain significance	not provided	2015-10-28	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3679A>T at the cDNA level, p.Ile1227Leu (I1227L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile1227Leu 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 Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ile1227Leu occurs at a position that is conserved across species and is located within domain V of the MutS domain (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 Ile1227Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574037	SCV000662547	uncertain significance	Hereditary cancer-predisposing syndrome	2017-03-13	criteria provided, single submitter	clinical testing	The p.I1227L variant (also known as c.3679A>T), located in coding exon 8 of the MSH6 gene, results from an A to T substitution at nucleotide position 3679. The isoleucine at codon 1227 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. In addition, the CoDP in silico tool predicts this alteration to have moderate impact on molecular function, with a score of 0.619 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625244	SCV000744301	uncertain significance	Lynch syndrome 5	2017-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574037	SCV000908429	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854284	SCV002225827	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004566922	SCV005054919	uncertain significance	Endometrial carcinoma	2024-02-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625244	SCV000745654	uncertain significance	Lynch syndrome 5	2017-05-21	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000217680	SCV001962725	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000217680	SCV002035828	uncertain significance	not provided		no assertion criteria provided	clinical testing