Submissions for variant NM_000179.3(MSH6):c.4043A>C (p.Glu1348Ala)

gnomAD frequency: 0.00001  dbSNP: rs1449733937

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000630206	SCV000751162	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-31	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 525857). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1348 of the MSH6 protein (p.Glu1348Ala).
Fulgent Genetics, Fulgent Genetics	RCV000764437	SCV000895494	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021738	SCV001183389	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	The p.E1348A variant (also known as c.4043A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4043. The glutamic acid at codon 1348 is replaced by alanine, an amino acid with dissimilar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome. This individual was diagnosed with ovarian cancer at age 63 (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001775930	SCV002013165	uncertain significance	not provided	2020-09-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354879	SCV001549596	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Glu1348Ala variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, COSMIC, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu1348Ala residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.