ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.183G>T (p.Gln61His) (rs121913496)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000420806 SCV000505655 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440259 SCV000506599 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423449 SCV000506600 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433734 SCV000506601 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442468 SCV000506602 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421964 SCV000506603 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433099 SCV000506604 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444731 SCV000506605 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424686 SCV000506606 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434965 SCV000506607 likely pathogenic Neoplasm of the thyroid gland 2016-05-31 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000589258 SCV000698553 likely pathogenic Noonan syndrome 3 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The HRAS c.183G>T (p.Gln61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant alters a GEF interaction site of conserved H_Ras_like domain and was shown to have a reduced hydrolyzed GTPase activity resulting in a constitutively active protein (Bollag, 1991; Der 1986). The variant of interest is absent from broad control datasets of ExAC or gnomAD (~100996 and 276982 chrs tested, respectively). The variant has not, to our knowledge, been reported as germline mutation in individuals diagnosed with Costello (CS) or Noonan Spectrum Related Disorders (NSRD) via publications and/or reputable databases/clinical diagnostic laboratories. Oncogenic Ras codons 12, 13 and 61 are well known as the primary sites where activating somatic mutations result in a constitutively active protein characterized by a reduced GAP action and/or intrinsic GTPase activity. The p.Gln61His is vastly reported in the literature as a somatic variant, identified in melanoma, metaplastic breast carcinoma, lung cancer, head and neck cancer, and other types of tumors. The c.183G>T was identified in a prenatal sample with negative MCC referred for genetic testing due to abnormal ultrasound finding (cystic hygroma, fetal edema and cardiac defect). Considering all evidence and ACMG guidelines, the variant of interest is classified as Likely Pathogenic.

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