NM_005343.4(HRAS):c.191_217dup (p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002254473.2

Allele description [Variation Report for NM_005343.4(HRAS):c.191_217dup (p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet)]

NM_005343.4(HRAS):c.191_217dup (p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet)

Genes:

HRAS:HRas proto-oncogene, GTPase [Gene - OMIM - HGNC]
LRRC56:leucine rich repeat containing 56 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_005343.4(HRAS):c.191_217dup (p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet)

HGVS:

NC_000011.10:g.533839_533865dup
NG_007666.1:g.6686_6712dup
NM_001130442.3:c.191_217dup
NM_001318054.2:c.-129_-103dup
NM_005343.4:c.191_217dupMANE SELECT
NM_176795.5:c.191_217dup
NP_001123914.1:p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet
NP_005334.1:p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet
NP_789765.1:p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet
LRG_506t1:c.191_217dup
LRG_506:g.6686_6712dup
LRG_506p1:p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet
NC_000011.9:g.533839_533865dup
NM_176795.3:c.191_217dup27

Links:

dbSNP: rs2133990580

NCBI 1000 Genomes Browser:

rs2133990580

Molecular consequence:

NM_001318054.2:c.-129_-103dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.191_217dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_005343.4:c.191_217dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_176795.5:c.191_217dup - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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MAN1A2 [Aquila chrysaetos chrysaetos]
MAN1A2 [Aquila chrysaetos chrysaetos]
Gene ID:115343773

Gene
CNTN1 [Leptonychotes weddellii]
CNTN1 [Leptonychotes weddellii]
Gene ID:102735100

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525672	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 17, 2022)	somatic	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525672

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 17, 2022)

somatic

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002525672.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

A likely pathogenic variant was identified in exon 3 of HRAS (NM_005343.2:c.191_217dup27, p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet). This variant was detected in 1.2% of reads, consistent with somatic origin. This variant is absent from the medical literature and the general population (gnomAD v2.1.1) The duplication of 27 base pairs causes an in-frame insertion of nine amino acids in the HRAS switch II domain, a region critical for binding regulator and effector proteins (PMID: 11701921). Although the c.191_217dup27 variant has not been previously reported, in-frame insertions and duplications within the switch II domain have been reported in individuals with arteriovenous malformations (PMID: 31637524) and RASopathies (PMID: 31160609, PMID: 23335589). In addition, functional analyses of similar in-frame insertions and duplications in the HRAS switch II domain have demonstrated that these variants lead to increased RAS signaling (PMID: 31160609, PMID: 23335589)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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