ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1070A>C (p.Glu357Ala) (rs150503781)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168008 SCV000218659 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 357 of the MSH2 protein (p.Glu357Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with ovarian, fallopian tube, or peritoneal carcinoma (PMID: 22006311). ClinVar contains an entry for this variant (Variation ID: 188133). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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 RCV000236761 SCV000293020 uncertain significance not provided 2015-07-16 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1070A>C at the cDNA level, p.Glu357Ala (E357A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu357Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu357Ala occurs at a position that is conserved across species and is located in the lever domain (Lutzen 2008). 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 MSH2 Glu357Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568153 SCV000662280 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000568153 SCV000684901 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000662371 SCV000784764 uncertain significance Lynch syndrome I 2017-11-13 criteria provided, single submitter clinical testing

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