Submissions for variant NM_000179.3(MSH6):c.2664G>C (p.Lys888Asn)

gnomAD frequency: 0.00002  dbSNP: rs730881798

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759138	SCV000211300	uncertain significance	not provided	2022-11-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and/or ovarian cancer (Maxwell et al., 2016); This variant is associated with the following publications: (PMID: 17531815, 21120944, 27153395)
Ambry Genetics	RCV000160683	SCV000213658	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The p.K888N variant (also known as c.2664G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2664. The lysine at codon 888 is replaced by asparagine, an amino acid with 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	RCV000205971	SCV000261292	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160683	SCV000685306	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 888 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 hereditary cancer in the literature. This variant has been identified in 2/250488 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759138	SCV000888264	uncertain significance	not provided	2017-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781587	SCV000919752	uncertain significance	not specified	2018-07-10	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2664G>C (p.Lys888Asn) results in a non-conservative amino acid change located in the DNA mismatch repair ATPase MutS domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 245364 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.2664G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Illumina Laboratory Services, Illumina	RCV001142302	SCV001302727	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759138	SCV003799915	uncertain significance	not provided	2022-02-28	criteria provided, single submitter	clinical testing	The MSH6 c.2664G>C; p.Lys888Asn variant (rs730881798) is reported in the literature in a large breast cancer cohort, but without clear association with disease (Maxwell 2016). This variant is also reported in ClinVar (Variation ID: 182637), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 888 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.228). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. PMID: 27153395.
Baylor Genetics	RCV003462094	SCV004197689	uncertain significance	Endometrial carcinoma	2023-09-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998497	SCV004838438	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 888 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 hereditary cancer in the literature. This variant has been identified in 2/250488 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001142302	SCV002568089	likely benign	Lynch syndrome 5	2020-10-22	no assertion criteria provided	clinical testing	This variant has conflicting interpretations in ClinVar (Variation ID 182637). Based on in silico scores, the MSH6 variant c.2664G>C (p.K888N) has a prior probability of pathogenicity of 10% (Thompson 2013). Cosegregation anaylsis in one family was performed and demonstrates that this variant has a likelihood ratio of 0.1967 (Thompson 2003). Bayesian analysis integrating all of this data gives about a 2% probability of pathogenicity (Tavtigian 2018), which is consistent with a classification of likely benign.