Variant: NM_001754.5(RUNX1):c.300C>G (p.Ser100=)

CA512318845

463991 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: e9ec7bd4-3aef-416c-9b22-48d87e0afa88

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.5:c.300C>G
NM_001754.5(RUNX1):c.300C>G (p.Ser100=)
NC_000021.9:g.34886894G>C
CM000683.2:g.34886894G>C
NC_000021.8:g.36259191G>C
CM000683.1:g.36259191G>C
NC_000021.7:g.35181061G>C
NG_011402.2:g.1102818C>G
ENST00000675419.1:c.300C>G
ENST00000300305.7:c.300C>G
ENST00000344691.8:c.219C>G
ENST00000358356.9:c.219C>G
ENST00000399237.6:c.264C>G
ENST00000399240.5:c.219C>G
ENST00000437180.5:c.300C>G
ENST00000455571.5:c.261C>G
ENST00000482318.5:c.59-6181C>G
NM_001001890.2:c.219C>G
NM_001122607.1:c.219C>G
NM_001754.4:c.300C>G
NM_001001890.3:c.219C>G
NM_001122607.2:c.219C>G

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: PM2_Supporting BP7 BP4

• Not Met criteria codes: BS2 BS4 BS3 BS1 PVS1 BP5 BP2 BP3 BP1 PS4 PS2 PS3 PS1 PP1 PP4 PP3 PP2 BA1 PM1 PM5 PM3 PM4 PM6

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.300C>G (p.Ser100=) is a synonymous variant. In summary, this variant meets the criteria to be classified as likely benign. Therefore, a REVEL score is not calculable. SpliceAI prediction suggests Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. Therefore, there appears to be no effect on splicing (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.302402 < 2.0)(BP7 ). This variant is completely absent from all population databases with at least 20x coverage for RUNX1(PM2_supporting). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1. Therefore, PM2 is MET.
• BP7: This is a synonymous variant with no effect on the final amino acid codon. Therefore, a REVEL score is not calculable. SpliceAI prediction suggests: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. Therefore, there appears to be no effect on splicing. Given the above, PP3 is NOT MET. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.302402 < 2.0). Therefore, BP7 IS MET.
• BP4: This is a synonymous variant with no effect on the final amino acid codon. Therefore, a REVEL score is not calculable. SpliceAI prediction suggests: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. Therefore, there appears to be no effect on splicing. Given the above, BP4 is MET.

Not Met criteria codes

• BS2: This rule is not applicable for MM-VCEP
• BS4: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no segregation studies available. BS4 is NOT MET.
• BS3: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no functional studies available. BS3 is NOT MET.
• BS1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1. Therefore, BS1 is NOT MET.
• PVS1: This is a synonymous variant, therefore PVS1 is NOT MET.
• BP5: This rule is not applicable for MM-VCEP
• BP2: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no inheritance data from studies available. BP2 is NOT MET.
• BP3: This rule is not applicable for MM-VCEP
• BP1: This rule is not applicable for MM-VCEP
• PS4: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no allele burden data from studies available. PS4 is NOT MET.
• PS2: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no de novo data from studies available. PS2 is NOT MET.
• PS3: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no functional studies available. BS3 is NOT MET.
• PS1: This is not applicable for a synonymous variant
• PP1: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no segregation studies available. PP1 is NOT MET.
• PP4: This rule is not applicable for MM-VCEP
• PP3: This is a synonymous variant with no effect on the final amino acid codon. Therefore, a REVEL score is not calculable. SpliceAI prediction suggests: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. Therefore, there appears to be no effect on splicing. Given the above, PP3 is NOT MET.
• PP2: This rule is not applicable for MM-VCEP
• BA1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1. Therefore, BA1 is NOT MET.
• PM1: This is not applicable for a synonymous variant
• PM5: This is not applicable for a synonymous variant
• PM3: This rule is not applicable for MM-VCEP
• PM4: This is a synonymous variant, which not result in a protein length altering variant. Therefore, PM4 is NOT MET.
• PM6: An extensive literature search of PubMed, Google Scholar, and Mastermind revealed no literature on this variant. Therefore, there are no de novo data from studies available. PM6 is NOT MET.