Submissions for variant NM_000179.3(MSH6):c.2753A>G (p.His918Arg)

dbSNP: rs754948438

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480774	SCV000565227	uncertain significance	not provided	2015-02-16	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2753A>G at the cDNA level, p.His918Arg (H918R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 His918Arg 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 Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH6 His918Arg occurs at a position that is highly conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 His918Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000774604	SCV000908404	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 918 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 been identified in 1/251002 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	RCV001071302	SCV001236597	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000774604	SCV002750279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.H918R variant (also known as c.2753A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2753. The histidine at codon 918 is replaced by arginine, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387852	SCV004099915	uncertain significance	not specified	2023-09-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470525	SCV004195756	uncertain significance	Endometrial carcinoma	2023-05-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002247	SCV004840840	uncertain significance	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 918 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). 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 1/251002 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.