NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser) AND Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 24, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001290696.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser)]

NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser)

Genes:

RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
RUNX1-AS1:RUNX1 antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser)

Other names:

NM_001754.5(RUNX1):c.486G>C; p.Arg162Ser

HGVS:

NC_000021.9:g.34880579C>G
NG_011402.2:g.1109133G>C
NM_001001890.3:c.405G>C
NM_001122607.2:c.405G>C
NM_001754.5:c.486G>CMANE SELECT
NP_001001890.1:p.Arg135Ser
NP_001116079.1:p.Arg135Ser
NP_001745.2:p.Arg162Ser
LRG_482:g.1109133G>C
NC_000021.8:g.36252876C>G

Protein change:

R135S

Links:

dbSNP: rs1057519749

NCBI 1000 Genomes Browser:

rs1057519749

Molecular consequence:

NM_001001890.3:c.405G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.405G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.486G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Identifiers:: MONDO: MONDO:0011071; MedGen: CN281654

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Homo sapiens ubiquitously transcribed tetratricopeptide repeat containing, Y-lin...
Homo sapiens ubiquitously transcribed tetratricopeptide repeat containing, Y-linked (UTY), transcript variant 11, mRNA
gi|384871641|ref|NM_001258256.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001478833	ClinGen Myeloid Malignancy Variant Curation Expert Panel	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v2)	Likely Pathogenic (Jun 24, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478833

ClinGen Myeloid Malignancy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v2)

Likely Pathogenic
(Jun 24, 2024)

germline

curation

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV001478833.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376022, 376021) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>C variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376019) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5_supporting, PS1_moderate, PM2_supporting, PP3.

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

Last Updated: Jul 29, 2024

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