Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_004985.4(KRAS):c.15A>T (p.Lys5Asn)

CA234191

12594 (ClinVar)

Gene: KRAS

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 15c2f120-e3bd-4bf0-8ecb-86290c93de7c

HGVS expressions

NM_004985.4:c.15A>T

NM_004985.4(KRAS):c.15A>T (p.Lys5Asn)

NM_033360.3:c.15A>T

NM_001369786.1:c.15A>T

NM_001369787.1:c.15A>T

NM_004985.5:c.15A>T

NM_033360.4:c.15A>T

ENST00000256078.8:c.15A>T

ENST00000311936.7:c.15A>T

ENST00000556131.1:c.15A>T

ENST00000557334.5:c.15A>T

NC_000012.12:g.25245370T>A

CM000674.2:g.25245370T>A

NC_000012.11:g.25398304T>A

CM000674.1:g.25398304T>A

NC_000012.10:g.25289571T>A

NG_007524.1:g.10551A>T

NG_007524.2:g.10634A>T

Pathogenic

PM6_Strong PP3 PP2 PM2 PS4_Moderate

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.15A>T (p.Lys5Asn) variant in KRAS has been reported in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID: 17056636, GeneDx internal data). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Lys5Asn variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 17056636, GeneDx, EGL Genetics internal data, ClinVar SCV000202928.7). Computational prediction tools and conservation analysis suggest that the p.Lys5Asn variant may impact protein function (PP3). The variant is located in the KRAS gene, which 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, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM6_Strong, PM2, PP2, PP3.

PM6_Strong

The c.15A>T p.Lys5Asn variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID: 17056636, GeneDx internal data).

PP3

Computational prediction tools and conservation analysis suggest that the p.Lys5Asn variant may impact the protein (PP3).

PP2

The variant is located in the KRAS gene, which 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).

PM2

Absent from both versions of gnomAD.

PS4_Moderate

The p.Lys5Asn variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 17056636, GeneDx, EGL Genetics internal data, ClinVar SCV000202928.7).

Cases PubMed:17056636

Approved on: 2020-05-18

Published on: 2020-07-01

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