ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3442G>A (p.Gly1148Ser) (rs63750257)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478492 SCV000566526 uncertain significance not provided 2015-05-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3442G>A at the cDNA level, p.Gly1148Ser (G1148S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly1148Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly1148Ser occurs at a position that is conserved across species and is located within the ATP-binding motif (Kariola 2002). 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 Gly1148Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561997 SCV000673933 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000758613 SCV000887370 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.3442G>C has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Invitae RCV000820952 SCV000961691 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1148 of the MSH6 protein (p.Gly1148Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs63750257, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 419014). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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