Submissions for variant NM_000179.3(MSH6):c.667A>G (p.Asn223Asp)

gnomAD frequency: 0.00001  dbSNP: rs374041375

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223134	SCV000276752	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	The p.N223D variant (also known as c.667A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 667. The asparagine at codon 223 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000228836	SCV000283854	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223134	SCV000903539	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 223 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/249596 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201254	SCV001372356	uncertain significance	not specified	2020-06-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.667A>G (p.Asn223Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.667A>G has been reported in the literature in at least one individual affected with lung adenocarcinoma (Lu_2015). This report however does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462500	SCV004195678	uncertain significance	Endometrial carcinoma	2023-07-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997984	SCV004836775	uncertain significance	Lynch syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 223 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/249596 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355754	SCV001550721	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Asn223Asp variant was assessed to have no impact on the MSH6 protein using a bioinformatics tool CoDP (Combination of the Different Properties) that integrates the prediction results of MAPP, PolyPhen-2 and SIFT, in addition to 2 other structural properties (solvent accessibility and change in the number of heavy atoms of amino acids (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs374041375) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Ambry Genetics and Invitae), Clinvitae (2x), and in control databases in 2 of 244386 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 2 of 111096 chromosomes (freq: 0.00002), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was not identified in GeneInSight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The p.Asn223 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Asp impacts the protein; this information is not predictive enough to rule out 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.