Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001351834.2(ATM):c.3245_3247delinsTGAT (p.His1082fs)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA298025

3033 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 651f107f-be2a-48a5-9cf5-598843115cb2

Approved on: 2022-03-09

Published on: 2022-07-11

HGVS expressions

NM_001351834.2:c.3245_3247delinsTGAT

NM_001351834.2(ATM):c.3245_3247delinsTGAT (p.His1082fs)

NC_000011.10:g.108272813_108272815delinsTGAT

CM000673.2:g.108272813_108272815delinsTGAT

NC_000011.9:g.108143540_108143542delinsTGAT

CM000673.1:g.108143540_108143542delinsTGAT

NC_000011.8:g.107648750_107648752delinsTGAT

NG_009830.1:g.54982_54984delinsTGAT

ENST00000278616.9:c.3245_3247delinsTGAT

ENST00000683174.1:n.3395_3397delinsTGAT

ENST00000527805.6:c.3245_3247delinsTGAT

ENST00000675595.1:c.3080_3082delinsTGAT

ENST00000675843.1:c.3245_3247delinsTGAT

ENST00000278616.8:c.3245_3247delinsTGAT

ENST00000452508.6:c.3245_3247delinsTGAT

ENST00000527805.5:c.3245_3247delinsTGAT

NM_000051.3:c.3245_3247delinsTGAT

NM_001351834.1:c.3245_3247delinsTGAT

NM_000051.4:c.3245_3247delinsTGAT

NM_000051.4(ATM):c.3245_3247delinsTGAT (p.His1082fs)

Pathogenic

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

PM3_Very Strong PVS1 PM5_Supporting PM2_Supporting

Evidence Links 0

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

PM3_Very Strong

This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong >8.0 POINTS).

PVS1

This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1).

PM5_Supporting

In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting)

PM2_Supporting

Variant is absent in the GnomAD cohort (PM2_Supporting)

Curation History

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