ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.74G>A (p.Gly25Asp) (rs767747378)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164134 SCV000214749 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000525136 SCV000625458 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 25 of the MSH2 protein (p.Gly25Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual with a personal or family history of Lynch syndrome-related cancers in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 184810). 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 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.
Color RCV000164134 SCV000905801 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193893 SCV001363052 uncertain significance not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.74G>A (p.Gly25Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-06 in 219022 control chromosomes (gnomAD). 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.74G>A in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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