Submissions for variant NM_000179.3(MSH6):c.3235A>C (p.Ile1079Leu)

dbSNP: rs587779933

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115408	SCV000149317	uncertain significance	not provided	2014-02-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3235A>C at the cDNA level, p.Ile1079Leu (I1079L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile1079Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Ile1079Leu occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ile1079Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002444567	SCV002611328	likely benign	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593912	SCV004366234	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1079 of the MSH6 protein (p.Ile1079Leu). 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: 127583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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.
Baylor Genetics	RCV004567005	SCV005054930	uncertain significance	Endometrial carcinoma	2024-02-09	criteria provided, single submitter	clinical testing