Submissions for variant NM_005343.4(HRAS):c.181C>A (p.Gln61Lys)

dbSNP: rs28933406

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587258	SCV000698552	likely pathogenic	Noonan syndrome 3	2017-08-28	criteria provided, single submitter	clinical testing	Variant summary: The HRAS c.181C>A (p.Gln61Lys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120996 control chromosomes. This variant has been reported as somatic variant in many cancer samples and has been shown to strongly activate the transforming potential of HRAS gene and produce an 8-10 fold reduction in GTPase activity by functional study (Der_1986). This supports the role of inhibition of GTP hydrolysis resulting in a constitutively activated HRAS protein, consistent with the established mechanism of disease attributed to variants in the HRAS gene. In addition, codon Gln61 has been reported as a hotspot for transforming mutations (Saxowsky_2008), and variant was reported as a somatic variant by Database of Curated Mutations (DoCM) to Likely pathogenic. This variant has not, to our knowledge, been reported as a germline variant in patients with Noonan syndrome and related conditions. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
GeneDx	RCV000681435	SCV000808898	pathogenic	not provided	2018-08-16	criteria provided, single submitter	clinical testing	The Q61K missense variant in the HRAS gene has not been previously published as a germline variant in association with RASopathies. However, the Q61K variant is not observed in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution in the GTP nucleotide binding region, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (Q61R) and nearby residues (T58I, G60D/V, E63K) of HRAS have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014). Additionally, variants at the same codon in KRAS (Q61P) and NRAS (Q61P/H/R) have been reported, supporting the functional importance of this region of the protein. We interpret this variant as pathogenic
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004562206	SCV005049531	likely pathogenic	Epidermal nevus	2024-03-21	criteria provided, single submitter	clinical testing	An HRAS c.181C>A (p.Gln61Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in an individual with epidermal nevus (Huang L et al., PMID: 35567308). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic germline variant by two submitters (ClinVar ID: 12601) and has been reported as a somatic variant in multiple cases in the cancer database COSMIC (COSV54236740). This variant is absent from the general population (gnomAD v.4.0.0), indicating that it is not a common variant. Another variant in the same codon, (p.Gln61Arg), has been reported in two individuals with melanocytic nevus (Groesser L et al., PMID: 23337891). The HRAS c.181C>A (p.Gln61Lys) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.181C>A (p.Gln61Lys) variant is classified as likely pathogenic.
OMIM	RCV000013434	SCV000033681	pathogenic	Thyroid cancer, nonmedullary, 2	2009-11-01	no assertion criteria provided	literature only
OMIM	RCV000022795	SCV000044084	pathogenic	Spermatocytic seminoma	2009-11-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439343	SCV000505660	likely pathogenic	Breast neoplasm	2015-07-14	no assertion criteria provided	literature only
Institute of Medical Sciences, Banaras Hindu University	RCV001255683	SCV001432248	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research