Submissions for variant NM_000179.3(MSH6):c.3218C>G (p.Pro1073Arg)

gnomAD frequency: 0.00001  dbSNP: rs587779257

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484501	SCV000565231	uncertain significance	not provided	2014-12-17	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3218C>G at the cDNA level, p.Pro1073Arg (P1073R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). Terui et al. (2013) concluded that this variant had no impact on functionality of MSH6 based on a prediction model which included integration of in silico models and other structural properties. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence for classification (Thompson 2014). MSH6 Pro1073Arg 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 Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro1073Arg occurs at a position that is highly conserved through mammals and is located in the MutS domain (Terui 2013). 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 Pro1073Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001181943	SCV001347207	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1073 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 observed in a cohort of individuals affected by sporadic triple negative breast cancer (PMID: 30630526). This variant has been identified in 2/251354 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	RCV001209408	SCV001380840	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1073 of the MSH6 protein (p.Pro1073Arg). This variant is present in population databases (rs587779257, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 30630526). ClinVar contains an entry for this variant (Variation ID: 89355). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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.
All of Us Research Program, National Institutes of Health	RCV003997085	SCV004834995	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1073 of the MSH6 protein. Computational prediction tool 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251354 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.