Submissions for variant NM_000179.3(MSH6):c.3442G>A (p.Gly1148Ser)

dbSNP: rs63750257

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478492	SCV000566526	uncertain significance	not provided	2015-05-18	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3442G>A at the cDNA level, p.Gly1148Ser (G1148S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly1148Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly1148Ser occurs at a position that is conserved across species and is located within the ATP-binding motif (Kariola 2002). 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 Gly1148Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000561997	SCV000673933	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-28	criteria provided, single submitter	clinical testing	The p.G1148S variant (also known as c.3442G>A), located in coding exon 6 of the MSH6 gene, results from a G to A substitution at nucleotide position 3442. The glycine at codon 1148 is replaced by serine, an amino acid with 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758613	SCV000887370	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.3442G>C has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Invitae	RCV000820952	SCV000961691	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561997	SCV002053055	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1148 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 1/251430 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.
All of Us Research Program, National Institutes of Health	RCV000758613	SCV004835069	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1148 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 1/251430 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.