ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1211A>G (p.Asn404Ser) (rs768740986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460255 SCV000551048 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000520334 SCV000618478 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1211A>G at the cDNA level, p.Asn404Ser (N404S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in an individual with colon cancer (Pearlman 2016). MSH6 Asn404Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH6 Asn404Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located in the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Asn404Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567415 SCV000669933 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-25 criteria provided, single submitter clinical testing The p.N404S variant (also known as c.1211A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1211. The asparagine at codon 404 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in one individual, diagnosed with colon cancer at age 46, whose tumor demonstrated presence of the MSH6 protein (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is 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.
Color RCV000567415 SCV000685181 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing

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