Submissions for variant NM_000179.3(MSH6):c.1996T>C (p.Ser666Pro)

dbSNP: rs587779222

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593868	SCV004293908	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 666 of the MSH6 protein (p.Ser666Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 17854147). ClinVar contains an entry for this variant (Variation ID: 89236). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MSH6 function (PMID: 28531214). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357734	SCV001553290	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ser666Pro variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs587779222) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by an INSiGHT expert panel in 2013). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). Introduction of the variant into mouse embryonic stem cells did not alter MMR activity (Houlleberghs 2017). The p.Ser666 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.