2026 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #11

Submission information
Submission Number: 11
Submission ID: 183405
Submission UUID: 36a8d490-f725-4716-b4c7-f243b043213d
Submission URI: /egrp/seqspaceabstracts

Created: Fri, 06/12/2026 - 09:47
Completed: Fri, 06/12/2026 - 09:47
Changed: Fri, 06/12/2026 - 09:47

Remote IP address: 10.208.28.22
Submitted by: Anonymous
Language: English

Is draft: No
First Name Cerdan
Middle Initial G.
Last Name Lopez
Degree(s) MGH
Position/Title/Career Status Graduate Research Student
Organization University of Melbourne
Email cerdan.lopez@student.unimelb.edu.au
Abstract Title Addressing discordant classifications of MLH1, MSH2, and MSH6 missense, splice site, and frameshift variants on ClinVar using version 2 of the MMR gene specifications to the ACMG/AMP Criteria
Abstract Summary The ClinGen InSiGHT VCEP is charged with maintaining pathogenicity assignment currency of MMR variants on ClinVar. This study aims to re-curate discordant MLH1, MSH2, and MSH6 variants on ClinVar using the MMR-specific modifications to the ACMG/AMP criteria (v2.0), contemporary knowledge, and contact with submitting laboratories. Reasons for change in pathogenicity were analysed.

MLH1, MSH2, and MSH6 discordant variants recorded on ClinVar as of June 2026 were selected. Classification change likelihood was maximized by selecting: (A) missense, splice site, and frameshift; (B) documented association with GI cancers; (C) ≥0.81 prior; and (D) ≤0.00002 gnomAD v4.1 allele frequency. Submitting laboratories were contacted for further information. Literature was searched using Mastermind and LitVar2. Reclassification was done using the MMR-specific modifications to the ACMG/AMP criteria (v2.0). For MSH2, Jia et al., calibrated by Scott et al., was used to determine loss of function. For MLH1 and MSH6 the functional assay flowchart and spreadsheet from the modified criteria was used.

Thirty-one of 45 MLH1 variants, submitted as P/LP-VUS, were re-classified as VUS and 14 as LP. Just one of 35 B/LB-VUS variants was re-classified LB. Only 1 P/LP-B/LB variant was re-classified as VUS.
Two of 51 MSH2 variants, previously submitted as P/LP-VUS, were re-classified as P, 35 as LP, and 14 as VUS. Eighty-one of 84 B/LB-VUS variants were re-classified as VUS, 2 as LP, and 2 as LB.
Fifteen of 48 MSH6 variants, submitted as P/LP-VUS, were re-classified as LP and 33 as VUS. Four B/LB-VUS variants were reclassified as VUS.
Most submitting laboratories had little new information to add. Tumour microsatellite information was most useful for re-classification.

This study provides a framework for systematically addressing discordant variants recorded on ClinVar to assist the ClinGen InSiGHT VCEP’s legacy responsibilities. Lack of updated detailed literature, familial studies, and functional data often limits reclassification.