ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.968C>T (p.Ser323Phe) (rs63750732)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166896 SCV000217713 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000472836 SCV000548181 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 323 of the MSH2 protein (p.Ser323Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual undergoing multigene hereditary-cancer panel testing (PMID: 27720647). ClinVar contains an entry for this variant (Variation ID: 187194). 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. 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.
GeneDx RCV000590192 SCV000566806 uncertain significance not provided 2017-04-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.968C>T at the cDNA level, p.Ser323Phe (S323F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser323Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ser323Phe occurs at a position that is not conserved and is located in the Lever domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ser323Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166896 SCV000690153 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590192 SCV000696295 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.968C>T (p.Ser323Phe) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121182 control chromosomes. The variant has been cited in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000662856 SCV000785731 uncertain significance Lynch syndrome I 2017-11-10 criteria provided, single submitter clinical testing

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