Submissions for variant NM_000179.3(MSH6):c.369A>T (p.Lys123Asn)

dbSNP: rs587782106

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130622	SCV000185498	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-09	criteria provided, single submitter	clinical testing	The p.K123N variant (also known as c.369A>T), located in coding exon 2 of the MSH6 gene, results from an A to T substitution at nucleotide position 369. The lysine at codon 123 is replaced by asparagine, an amino acid with similar properties. This variant has been reported in a male diagnosed with microsatellite stable colorectal cancer at age 54 and with a family history of colorectal cancer diagnosed in his father (Chubb D et al. J. Clin. Oncol., 2015 Feb;33:426-32). 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.
GeneDx	RCV000590479	SCV000211339	uncertain significance	not provided	2014-07-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.369A>T at the cDNA level, p.Lys123Asn (K123N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys123Asn 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys123Asn occurs at a position that is moderately conserved across species and is located within the PWWP domain (Terui 2013). 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 Lys123Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590479	SCV000695883	uncertain significance	not provided	2016-02-23	criteria provided, single submitter	clinical testing	Variant summary: This MSH6 variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Lysine (K) with a medium size and polar Asparagine (N). Two in silico tools predict the variant to be benign and two predict deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. It was observed in one CRC patient, however without strong evidence for pathogenicity (Chubb_JCO_2015). Functional studies assessing the functional impact of the variant on the protein were not published at the time of classification. Clinical laboratories via ClinVar classify variant as Uncertain significance (without evidence to independently evaluate). Due to the lack of strong clinical data or functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae	RCV000807593	SCV000947655	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 123 of the MSH6 protein (p.Lys123Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 141913). 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 with a negative predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health	RCV003998070	SCV004826666	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 123 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 familial colorectal cancer (PMID: 25559809). This variant has not been identified 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202268	SCV000257275	uncertain significance	not specified		no assertion criteria provided	research