Submissions for variant NM_000179.3(MSH6):c.260G>C (p.Ser87Thr)

dbSNP: rs1114167734

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491429	SCV000580214	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	The p.S87T variant (also known as c.260G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 260. The serine at codon 87 is replaced by threonine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856940	SCV002311991	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-04-09	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces serine with threonine at codon 87 of the MSH6 protein (p.Ser87Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428349). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
Baylor Genetics	RCV003470601	SCV004195600	uncertain significance	Endometrial carcinoma	2023-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV004722830	SCV005331947	likely pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a pediatric patient with non-Hodgkin lymphoma (PMID: 34308104); This variant is associated with the following publications: (PMID: 34308104)