RUNX1 VUS RECLASSIFICATION
A Collaborative Effort to Support RUNX1 VUS Reclassification
As part of our mission, we are working closely with the ClinGen Myeloid Malignancy Variant Curation Expert Panel (MMVCEP), the NIH RUNX1 Natural History Study, and the team at ConnectMyVariant to advance the classification of germline RUNX1 variants of uncertain significance (VUSs).
This initiative provides direct support to affected individuals and their families while also generating critical data to inform expert variant curation and improve clinical decision-making.
About ConnectMyVariant
ConnectMyVariant is a voluntary, no-cost program that assists individuals with germline variants by helping them:
Understand their variant and its potential health implications
Connect with others who carry the same variant
Facilitate cascade testing and family communication
Participate in efforts to generate data that can support variant reclassification
The program’s Family Outreach Navigators offer personalized guidance and support to help patients and their relatives navigate variant interpretation, identify at-risk family members, and share their variant and family health information in a way that contributes to research and clinical knowledge.
For families affected by germline RUNX1 VUSs, this effort provides psychosocial support and empowers them to actively participate in research. For the broader medical genetics community, it contributes valuable evidence that supports expert classification efforts, in particular through MMVCEP review.
Variant Classification: Overview of MMVCEP’s Role
RUNX1 variant interpretation is guided by the MMVCEP, which uses the ACMG/AMP guidelines with disease-specific adaptations. Variants are categorized as:
| Classification | What It Means |
|---|---|
| Pathogenic | Established evidence for disease causation |
| Likely Pathogenic | Strong evidence for disease relevance |
| Variant of Uncertain Significance (VUS) | Insufficient or conflicting evidence regarding impact |
| Likely Benign | Strong evidence suggesting no impact |
| Benign | Established evidence that the variant is not disease-causing |
VUSs present a clinical challenge. Many patients and providers are left without clear guidance for surveillance or cascade testing. In collaboration with ConnectMyVariant and the NIH, we aim to collect the kind of familial and functional data that can resolve uncertain classifications. Identification of other individuals with the same variant, particularly across family lines, is key to enabling accurate reclassification.
Our Current Focus: Prioritized Germline RUNX1 VUSs
Currently, we are triaging and recruiting individuals with specific germline RUNX1 VUSs that have been identified by MMVCEP and collaborating researchers as having sufficient evidence to be considered for reclassification with additional familial or population data. We are reaching out to clinicians, genetic counselors, and researchers who may have patients with these variants and encouraging participation in the ConnectMyVariant program.
How You Can Help
We welcome collaboration from clinical partners and ask for your support in the following ways:
Identify patients with prioritized RUNX1 VUSs. If your patient carries a VUS under active review, we would be glad to coordinate next steps for potential engagement with ConnectMyVariant.
Share cases of any RUNX1 VUSs. While our current focus is on a prioritized list, we are building a pipeline for future evaluation and welcome information on other RUNX1 VUSs for inclusion in subsequent phases.
Provide a brief variant context. If possible, include the RUNX1 variant identified and whether the patient has a personal or family history consistent with RUNX1-FPD (e.g., thrombocytopenia, bleeding tendency, hematologic malignancy).
| Currently Prioritized Variants | ||
|---|---|---|
| c.305T>A (p.Leu102Gln) | c.1093G>C (p.Gly365Arg) | c.1164del (p.Ser389ArgfsTer) |
| c.1243C>T (p.Gln415Ter) | c.1264G>T (p.Glu422Ter) | c.296G>A (p.Cys99Tyr) |
| c.314A>C (p.His105Pro) | c.318G>T (p.Trp106Cys) | c.319C>A (p.Arg107Ser) |
| c.328A>C (p.Lys110Gln) | c.403G>A (p.Gly135Ser) | c.422C>T (p.Ser141Leu) |
| c.425C>A (p.Ala142Asp) | c.433A>G (p.Arg145Gly) | c.466G>A (p.Ala156Thr) |
| c.477T>G (p.Asn159Lys) | c.484_485delinsGC (p.Arg162Ala) | c.485G>A (p.Arg162Lys) |
| c.493G>C (p.Gly165Arg) | c.499A>G (p.Ser167Gly) | c.500G>C (p.Ser167Thr) |
| c.503G>A (p.Gly168Glu) | c.505A>G (p.Arg169Gly) | c.508G>C (p.Gly170Arg) |
| c.509-1G>A | c.509-3C>G | c.509G>A (p.Gly170Glu) |
| c.532A>C (p.Thr178Pro) | c.559G>A (p.Ala187Thr) | c.578T>A (p.Ile193Asn) |
| c.581A>C (p.Lys194Thr) | c.581A>T (p.Lys194Ile) | c.582A>C (p.Lys194Asn) |
| c.595G>A (p.Gly199Arg) | c.596G>C (p.Gly199Ala) | c.613+1G>A |
| c.805+1G>T | c.952dup (p.Ser318PhefsTer) | c.967+5G>A |
| c.968-2A>G |
Contact and Collaboration
If you are working with a patient who may benefit from the ConnectMyVariant program or would like to discuss specific RUNX1 variants or cases, please don’t hesitate to contact:
Katrin Ericson, PhD
Executive Director, RUNX1 Research Program
Email: kericson@runx1-fpd.org
We are happy to discuss case-specific details, provide patient materials, or coordinate direct communication between your patient and the ConnectMyVariant team. Thank you for your commitment to improving outcomes for individuals with inherited hematologic risk.