Evidence Repository
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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  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.485G>A (p.Arg162Lys)

CA16602490

376021 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c20346bb-711e-4d5f-bf45-8f14822fa448

HGVS expressions

NM_001754.4:c.485G>A
NM_001754.4(RUNX1):c.485G>A (p.Arg162Lys)
NC_000021.9:g.34880580C>T
CM000683.2:g.34880580C>T
NC_000021.8:g.36252877C>T
CM000683.1:g.36252877C>T
NC_000021.7:g.35174747C>T
NG_011402.2:g.1109132G>A
NM_001001890.2:c.404G>A
NM_001122607.1:c.404G>A
NM_001001890.3:c.404G>A
NM_001122607.2:c.404G>A
NM_001754.5:c.485G>A
ENST00000300305.7:c.485G>A
ENST00000344691.8:c.404G>A
ENST00000358356.9:c.404G>A
ENST00000399237.6:c.449G>A
ENST00000399240.5:c.404G>A
ENST00000437180.5:c.485G>A
ENST00000482318.5:c.*75G>A

Likely Pathogenic

Met criteria codes 4
PP3 PM1 PM2 PM5_Supporting
Not Met criteria codes 14
PS3 PS1 BP7 BP4 BP2 PP1 BA1 PM4 PM6 PVS1 PS4_Supporting BS1 BS3 BS4

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant by SCV001203102.1 in a proband (70s) with thrombocytopenia and anemia; however, the germline origins were not confirmed in this case and all other reports of the variant (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). The variant is located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) [PM1]. Although this variant has not been functionally evaluated, computational evidence supports a deleterious effect of this variant [PP3] and another missense variant at the same residue (i.e. p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP [PM5_supporting]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2, PM5_supporting, and PP3.
Met criteria codes
PP3
REVEL score=0.949, which is >0.75 threshold. SSF shows loss of a putative cryptic donor splice site at c.485, whereas MES shows a -72.3% score change (just below threshold for significance).
PM1
Located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is defined a hotspot (PMID: 31648317, 27294619, 23958918).
"The mutations occurring in these residues, such asR80C, R80G, K83Q, K83R, R135K, R135S, R139Q, R139L, D171Y, D171G, and R174Q detected in this study, would result in loss of hydrogen bonding interaction to DNA or disruption of the folding architecture of RUNX1; additional S114P and S114W were supposed to abolish heterodimerization with CBF-β.39" However, the cited article (PMID: 11257229) does not include this variant in its evaluation." PubMed:19808697
PM2
Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
PM5_Supporting
R162G is classified as likely pathogenic by the ClinGen MM-VCEP.
Not Met criteria codes
PS3
While there is functional data for this variant (PMID: 25840971; 9533875), it does not meet the thresholds set for even PS3_moderate, which requires reduced transactivation to at least 20% of WT or impact in 2 secondary assays.
Arg135Lys did not affect DNA-binding (Fig. 1A - maybe partial effect) or CBFb dimerization (Fig. 2A). However, it impaired C-FMS activation/protein expression compared to wildtype but comparable to the negative control (transactivation was ~25-35% of WT) (Fig. 3D/E) and the authors defined it as a low-activity mutation (activity < 0.520). Note that the variant is also correlated with sAML transformation (Table 1). PubMed:25840971
PS1
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
BP4
REVEL score=0.949, which is >0.75 threshold.
BP2
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
BA1
Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4_Supporting
Invitae tested a proband (70s) with thrombocytopenia and anemia, who didn't have a suggestive family history; however, the variant was not confirmed in the germline. There are published reports of this variant in patients with hematological neoplasm, but either somatic status has been confirmed or germline origin is again unknown (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). Furthermore, R162K has been considered one of the most recurrent somatic missense variants in sporadic AML based on not being observed in a cohort with 103 germline SNV (p<0.05) (PMID: 32208489).
BS1
Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS3
Arg135Lys did not affect DNA-binding (Fig. 1A - maybe partial effect) or CBFb dimerization (Fig. 2A). However, it impaired C-FMS activation/protein expression compared to wildtype but comparable to the negative control (transactivation was ~25-35% of WT) (Fig. 3D/E) and the authors defined it as a low-activity mutation (activity < 0.520). Note that the variant is also correlated with sAML transformation (Table 1). PubMed:25840971
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-01-12
Published on: 2021-01-12
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