ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1646C>A (p.Ser549Tyr)

gnomAD frequency: 0.00001  dbSNP: rs200447622
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115379 SCV000149288 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1646C>A at the cDNA level, p.Ser549Tyr (S549Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser549Tyr 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 Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. MSH6 Ser549Tyr occurs at a position that is not conserved across species and is located in the MSH2 binding site (Kariola 2002). In silico analyses 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 Ser549Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000546737 SCV000624673 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575160 SCV000662496 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-01 criteria provided, single submitter clinical testing The p.S549Y variant (also known as c.1646C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1646. The serine at codon 549 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is not well 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.
All of Us Research Program, National Institutes of Health RCV003997235 SCV004841813 uncertain significance Lynch syndrome 2023-03-23 criteria provided, single submitter clinical testing This missense variant replaces serine with tyrosine at codon 549 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 2/251118 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.

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