Variant: NM_005343.3(HRAS):c.508A>T (p.Lys170Ter)

CA296052

40447 (ClinVar)

Gene: HRAS

Condition: Costello syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 073e5f90-a343-456a-b175-656a2f84718f

Approved on: 2019-06-27

Published on: 2019-06-28

HGVS expressions

NM_005343.3:c.508A>T
NM_005343.3(HRAS):c.508A>T (p.Lys170Ter)
NC_000011.10:g.532698T>A
CM000673.2:g.532698T>A
NC_000011.9:g.532698T>A
CM000673.1:g.532698T>A
NC_000011.8:g.522698T>A
NG_007666.1:g.7853A>T
NM_001130442.1:c.508A>T
NM_005343.2:c.508A>T
NM_176795.3:c.*77A>T
NM_001130442.2:c.508A>T
NM_001318054.1:c.271A>T
NM_176795.4:c.*77A>T
NM_005343.4:c.508A>T
ENST00000311189.7:c.508A>T
ENST00000397594.5:c.*77A>T
ENST00000397596.6:c.508A>T
ENST00000417302.5:c.*77A>T
ENST00000451590.5:c.508A>T
ENST00000462734.1:n.283A>T
ENST00000478324.5:n.243-68A>T
ENST00000479482.1:n.429A>T
ENST00000493230.5:c.*77A>T

Uncertain Significance

• Met criteria codes: BS4

• Not Met criteria codes: BS2 BS1 BS3 BP7 BP5 BP1 BP4 BP3 BP2 BA1 PS1 PS2 PS4 PS3 PP2 PP3 PP1 PM5 PM4 PM1 PM2 PM6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.508A>T (p.Lys170Ter) variant in the HRAS gene has been identified in patients with cancer and individuals who underwent testing for RASopathies, however it was also identified in an unaffected parent (BS4; Invitae, GeneDx internal data, GTR Lab ID: 26957, 500031; SCV000207840.14, SCV000635092.3). The filtering allele frequency of the p.Lys170Ter variant is 0.0034% for European (non-Finnish) chromosomes by the gnomAD aggregation database (8/249358 with 95% CI), which is not a high enough frequency to meet thresholds defined by the ClinGen RASopahty Expert panel for autosomal dominant RASopathy variants (BA1/BS1 not met). Furthermore, LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore the PVS1 rule is not applicable. In summary, the clinical significance of the p.Lys170Ter variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4.

Met criteria codes

• BS4: GeneDx: Variant was identified in an unaffected parent

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: This variant has been detected in 8/125228 (0.00006) European (Non-Finnish) chromosomes which does not meet any of the cutoffs for frequency data. Note, GeneDx said that this met their criteria for BP_D.
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: This variant has been detected in 8/125228 (0.00006) European (Non-Finnish) chromosomes which does not meet any of the cutoffs for frequency data.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Invitae: We know that the molecular mechanism for HRAS is gain-of-function, and we haven’t observed this variant in anyone with Costello syndrome. We have seen it in several adults diagnosed with breast cancer, prostate cancer, or colon cancer. However, we haven’t conclusively established that LoF variants are not causative of disease which is why we are keeping them at VUS.
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: This variant has been detected in 8/125228 (0.00006) European (Non-Finnish) chromosomes which does not meet any of the cutoffs for frequency data.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline