Submissions for variant NM_000179.3(MSH6):c.1999G>C (p.Asp667His)

gnomAD frequency: 0.00001  dbSNP: rs151086192

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160675	SCV000211286	uncertain significance	not provided	2020-10-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23621914, 26691941)
Ambry Genetics	RCV000214441	SCV000276953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-21	criteria provided, single submitter	clinical testing	The p.D667H variant (also known as c.1999G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1999. The aspartic acid at codon 667 is replaced by histidine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). 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.
Invitae	RCV000233389	SCV000283738	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 667 of the MSH6 protein (p.Asp667His). This variant is present in population databases (rs151086192, gnomAD 0.0009%). 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: 182630). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). 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.
Counsyl	RCV000662835	SCV000785693	uncertain significance	Lynch syndrome 5	2017-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214441	SCV000904017	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 667 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 2/251046 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.
Myriad Genetics, Inc.	RCV000662835	SCV004019012	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV003998495	SCV004838247	uncertain significance	Lynch syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 667 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 2/251046 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.