ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.160G>T (p.Ala54Ser) (rs749212640)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164978 SCV000215671 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000200570 SCV000254388 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 54 of the MSH2 protein (p.Ala54Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs749212640, ExAC 0.008%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 185536). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000663139 SCV000786286 uncertain significance Lynch syndrome I 2018-04-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781570 SCV000919722 uncertain significance not specified 2018-11-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.160G>T (p.Ala54Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 228468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.160G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000781570 SCV001160017 uncertain significance not specified 2018-10-16 criteria provided, single submitter clinical testing The MSH2 c.160G>T; p.Ala54Ser variant (rs749212640) is reported as a variant of uncertain significance in the medical literature (DeRycke 2017). The variant is described as a variant of uncertain significance in the ClinVar database (Variation ID: 185536) the variant is found in the general population with an allele frequency of 0.0004% (1/228144 alleles) in the Genome Aggregation Database. The alanine at this position is highly conserved but computational analyses (SIFT: Tolerated, PolyPhen-2:Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is classified as a variant of uncertain significance.

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