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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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_001754.5:c.257C>T

CA410203786

1450492 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ef6b4aa0-2d9b-406b-bfe0-586da032d7ec
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_001754.5:c.257C>T
NC_000021.9:g.34886937G>A
CM000683.2:g.34886937G>A
NC_000021.8:g.36259234G>A
CM000683.1:g.36259234G>A
NC_000021.7:g.35181104G>A
NG_011402.2:g.1102775C>T
ENST00000675419.1:c.257C>T
ENST00000300305.7:c.257C>T
ENST00000344691.8:c.176C>T
ENST00000358356.9:c.176C>T
ENST00000399237.6:c.221C>T
ENST00000399240.5:c.176C>T
ENST00000437180.5:c.257C>T
ENST00000455571.5:c.218C>T
ENST00000482318.5:c.59-6224C>T
NM_001001890.2:c.176C>T
NM_001122607.1:c.176C>T
NM_001754.4:c.257C>T
NM_001001890.3:c.176C>T
NM_001122607.2:c.176C>T

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 25
PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PM1 PM5 PM3 PM4 PS2 PS4 PS1 PS3 PM6 BA1 PP1 PP4 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.257C>T (p.Pro86Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant has been published in a patient with AML M0 as a potentially homozygous variant (PMID: 17485549) and in a 73-year-old male with CMML along with R135S (PMID: 20421268 ), but germline origin is unclear for both cases; it was also detected in a patient with personal and family history of early-onset breast cancer (MSK-IMPACT at Memorial Sloan Kettering Cancer Center). It is not located at a hotspot or critical region of the Runt Homology Domain. The REVEL score is 0.854 and there is no splicing impact per SpliceAI. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting.
Met criteria codes
PM2_Supporting
Absent from gnomAD (v2 and v3) with at least 20x coverage.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Not applicable
BS4
No familial studies identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
BS3
No functional data identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
BS1
Absent from gnomAD (v2 and v3) with at least 20x coverage.
BP2
The variant has been published in a patient with AML M0 as a potentially homozygous variant (17485549) and in a 73yo male with CMML along with R135S (20421268:S3), but germline origin and phasing is unclear.
BP3
Not applicable
BP4
REVEL score = 0.854, which is higher than the v2 threshold of 0.50. There is no splicing impact per SpliceAI (Δ scores ≤ 0.20).
BP1
Not applicable
BP5
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM5
No other variants at P86 or P59 detected in HGMD or COSMIC. There may be reports of P86S, but only found in ~3 supplemental tables per Mastermind Basic.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No germline confirmed cases identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
PS4
The variant has been published in a patient with AML M0 as a potentially homozygous variant (17485549) and in a 73yo male with CMML along with R135S (20421268:S3), but germline origin is unclear for both cases. It was also detected in an MSKCC patient with personal and family history of early-onset breast cancer.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional data identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
PM6
No germline confirmed cases identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
BA1
Absent from gnomAD (v2 and v3) with at least 20x coverage.
PP1
No familial studies identified in the literature, including LOVD, HGMD, COSMIC, Mastermind, or Google/Google Scholar.
PP4
Not applicable
PP3
REVEL score = 0.854, which is lower than the v2 threshold of 0.88. There is no splicing impact per SpliceAI (Δ scores ≤ 0.20).
PP2
Not applicable
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