ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.415C>G (p.Pro139Ala) (rs779562531)

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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 RCV000166916 SCV000217735 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662504 SCV000785028 uncertain significance Lynch syndrome II 2017-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000521531 SCV000617972 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.415C>G at the cDNA level, p.Pro139Ala (P139A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has been reported in at least one individual with ovarian cancer (Shirts 2016). MLH1 Pro139Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Pro139Ala occurs at a position that is conserved across species and is located in 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 evidence, it is unclear whether MLH1 Pro139Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000524299 SCV000259548 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 139 of the MLH1 protein (p.Pro139Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs779562531, ExAC 0.001%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 187211). 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: "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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000204264 SCV000266181 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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