ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.945C>G (p.His315Gln) (rs587779959)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115488 SCV000149397 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.945C>G at the cDNA level, p.His315Gln (H315Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant has been identified in at least one individual with breast cancer and one individual with polyps and a family history of colon and pancreatic cancer (Maxwell 2015, Shirts 2016). MLH1 His315Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 His315Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524323 SCV000166258 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 315 of the MLH1 protein (p.His315Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs587779959, ExAC 0.003%). This variant has been reported in an individual affected with breast cancer (PMID: 25503501), as well as in an individual with family history of colon and pancreatic cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 127623). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000122978 SCV000266183 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568893 SCV000662014 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000568893 SCV000911072 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-14 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253192 SCV001428786 uncertain significance Duchenne muscular dystrophy 2019-06-04 criteria provided, single submitter clinical testing

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