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]

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Variant: NM_000051.3(ATM):c.3284G>A (p.Arg1095Lys)

CA165678

141522 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f902c885-8b6e-4e29-a3bb-2b52a3a53330

Approved on: 2022-03-09

Published on: 2022-07-11

HGVS expressions

NM_000051.3:c.3284G>A

NM_000051.3(ATM):c.3284G>A (p.Arg1095Lys)

NC_000011.10:g.108272852G>A

CM000673.2:g.108272852G>A

NC_000011.9:g.108143579G>A

CM000673.1:g.108143579G>A

NC_000011.8:g.107648789G>A

NG_009830.1:g.55021G>A

ENST00000278616.9:c.3284G>A

ENST00000683174.1:n.3434G>A

ENST00000527805.6:c.3284G>A

ENST00000675595.1:c.3119G>A

ENST00000675843.1:c.3284G>A

ENST00000278616.8:c.3284G>A

ENST00000452508.6:c.3284G>A

ENST00000527805.5:c.3284G>A

NM_001351834.1:c.3284G>A

NM_001351834.2:c.3284G>A

NM_000051.4:c.3284G>A

NM_000051.4(ATM):c.3284G>A (p.Arg1095Lys)

Uncertain Significance

PVS1_Strong PM2_Supporting

PP3

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.3284G>A (p.Arg1095Lys) variant is at the last nucleotide of an exon and is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1_Strong). This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

PVS1_Strong

This variant is at the last nucleotide of an exon and is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1_Strong).

PM2_Supporting

This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (PM2_Supporting).

PP3

In silico splicing predictors (SpliceAI donor loss Δ score: 0.84; MaxEntScan Δ: -8.15) predict that this alteration will have a significant impact on splicing (PP3). However, PP3 was not applied to avoid the double counting of predictive evidence used to support the application of PVS1_Strong.

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