ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.917A>T (p.Asn306Ile) (rs755553895)

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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 RCV000223630 SCV000275942 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbSNP, ESP, 1000 Genomes),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or Conflicting Evidence,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
GeneDx RCV000485727 SCV000565151 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.917A>T at the cDNA level, p.Asn306Ile (N306I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). This variant has been reported in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Castera 2014). MLH1 Asn306Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Asparagine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asn306Ile occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Asn306Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000223630 SCV000904892 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Invitae RCV000818768 SCV000959400 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 306 of the MLH1 protein (p.Asn306Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hereditary breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 231940). 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 disruptive, 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.

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