Submissions for variant NM_000179.3(MSH6):c.2950A>C (p.Asn984His)

gnomAD frequency: 0.00002  dbSNP: rs146359682

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166094	SCV000216860	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	The p.N984H variant (also known as c.2950A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2950. The asparagine at codon 984 is replaced by histidine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly 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.
Invitae	RCV000524150	SCV000260266	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000206584	SCV000296881	uncertain significance	Lynch syndrome	2015-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166094	SCV000685336	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 984 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 been reported in an individual affected with thyroid cancer (PMID: 29684080). This variant has been identified in 5/223886 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.
Counsyl	RCV000662779	SCV000785588	uncertain significance	Lynch syndrome 5	2017-09-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759855	SCV000889477	uncertain significance	not provided	2017-09-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662779	SCV001302729	uncertain significance	Lynch syndrome 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759855	SCV001470842	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing	The MSH6 c.2950A>C; p.Asn984His variant (rs146359682) is reported in ClinVar (Variation ID: 186492). This variant is found in the general population with an overall allele frequency of 0.002% (5/223886 alleles) in the Genome Aggregation Database. The asparagine at codon 984 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, a different bioinformatics tool (CoDP) developed specifically to predict the impact of missense variants on MSH6, suggests that this variant does not impact MSH6 protein (Terui 2013). However, given the lack of clinical and functional data, the significance of the p.Asn984His variant is uncertain at this time. REFERENCES Terui H et al. CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. J Biomed Sci. 2013 Apr 28;20:25.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375566	SCV001572452	uncertain significance	not specified	2021-04-04	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2950A>C (p.Asn984His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 223886 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2950A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000759855	SCV002526141	uncertain significance	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 23621914, 17531815, 21120944)
Myriad Genetics, Inc.	RCV000662779	SCV004018932	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003462200	SCV004197641	uncertain significance	Endometrial carcinoma	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000206584	SCV004839034	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 984 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 been reported in an individual affected with pancreatic cancer (PMID: 29684080). This variant has been identified in 5/223886 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.