Variant: NM_005343.3(HRAS):c.412G>A (p.Gly138Ser)

CA135988

45304 (ClinVar)

Gene: HRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 7b1915f1-7c70-4f7b-afa5-d08962f3c012

Approved on: 2019-07-25

Published on: 2019-07-26

HGVS expressions

NM_005343.3:c.412G>A
NM_005343.3(HRAS):c.412G>A (p.Gly138Ser)
NC_000011.10:g.533491C>T
CM000673.2:g.533491C>T
NC_000011.9:g.533491C>T
CM000673.1:g.533491C>T
NC_000011.8:g.523491C>T
NG_007666.1:g.7060G>A
ENST00000397594.7:c.412G>A
ENST00000417302.7:c.412G>A
ENST00000397594.6:c.130G>A
ENST00000417302.6:c.412G>A
ENST00000462734.2:c.412G>A
ENST00000311189.8:c.412G>A
ENST00000311189.7:c.412G>A
ENST00000397594.5:c.412G>A
ENST00000397596.6:c.412G>A
ENST00000417302.5:c.412G>A
ENST00000451590.5:c.412G>A
ENST00000462734.1:n.105G>A
ENST00000478324.5:n.122G>A
ENST00000479482.1:n.333G>A
ENST00000493230.5:c.412G>A
NM_001130442.1:c.412G>A
NM_005343.2:c.412G>A
NM_176795.3:c.412G>A
NM_001130442.2:c.412G>A
NM_001318054.1:c.93G>A
NM_176795.4:c.412G>A
NM_005343.4:c.412G>A
NM_001318054.2:c.93G>A
NM_001130442.3:c.412G>A
NM_176795.5:c.412G>A

Uncertain Significance

• Met criteria codes: PP2

• Not Met criteria codes: PS4 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.412G>A (p.Gly138Ser) variant in the HRAS gene has been identified in 1 Asian woman with Noonan Syndrome and 1 Asian man with Costello Syndrome (Laboratory for Molecular Medicine internal data). It has been also identified in 1 patient who had a combined cardiac panel (GeneDx internal data) and was observed in 3 unrelated women with breast cancer and 1 woman with uterine cancer (Invitae internal data). PS4_Supporting not met due to conflicting phenotypes between the identified patients. HRAS has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Gly138Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2.

Met criteria codes

• PP2: HRAS is a missense constrained gene

Not Met criteria codes

• PS4: Variant identified in 1 Asian woman with Noonan Syndrome and 1 Asian man with Costello Syndrome. Also identified in 1 patient in 2017 who had a combined cardiac panel (GeneDx internal data). Observed in 3 unrelated women with breast cancer and 1 woman with uterine cancer (Invitae internal data). PS4_Supporting not met due to conflicting phenotypes.
• PM2: Present in .0000193% CI 95% (2/18390) East Asian alleles in gnomAD