ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.954C>A (p.His318Gln) (rs146777069)

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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 RCV000167219 SCV000218056 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000702569 SCV000831428 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 318 of the MLH1 protein (p.His318Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 187486). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000167219 SCV001345270 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-03 criteria provided, single submitter clinical testing
Center of Medical Genetics and Primary Health Care RCV001005036 SCV000987293 uncertain significance Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A functional DNA Mismatch Repair domain (I216-334L aa), which is an ATP binding site. Hot-spot has 36 non-VUS coding variants (22 pathogenic and 14 benign), pathogenicity = 61.1%, proximity score 11.279 > threshold 2.472. PM2 Pathogenic Moderate: Variant not found in GnomAD exomes. Variant not found in GnomAD genomes. PP2 Pathogenic Supporting: 198 out of 264 non-VUS missense variants in gene MLH1 are pathogenic = 75.0% > threshold of 51.0%, and 914 out of 2,356 clinically reported variants in gene MLH1 are pathogenic = 38.8% > threshold of 12.0%. BP4 Benign Supporting: 6 benign predictions from DANN, EIGEN, FATHMM-MKL, MVP, PrimateAI and REVEL vs 5 pathogenic predictions from DEOGEN2, M-CAP, MutationAssessor, MutationTaster and SIFT and the position is not conserved. Therefore, it has been classified as a variant of uncertain significance.

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