ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2242G>A (p.Asp748Asn) (rs374380262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166895 SCV000217712 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Insufficient evidence
GeneDx RCV000483860 SCV000571857 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2242G>A at the cDNA level, p.Asp748Asn (D748N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). MLH1 Asp748Asn has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in an esophageal carcinoma according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. MLH1 Asp748Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Asp748Asn occurs at a position that is conserved across species and is located within the CTH motif (Pang 1997). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Asp748Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001070317 SCV001235539 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 748 of the MLH1 protein (p.Asp748Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187193). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

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