Variant: NM_000051.4(ATM):c.5858C>T (p.Thr1953Ile)

CA166228

141721 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 0382866e-7f85-4beb-bb92-417877e38547

Approved on: 2024-11-26

Published on: 2025-01-13

HGVS expressions

NM_000051.4:c.5858C>T
NM_000051.4(ATM):c.5858C>T (p.Thr1953Ile)
NC_000011.10:g.108310255C>T
CM000673.2:g.108310255C>T
NC_000011.9:g.108180982C>T
CM000673.1:g.108180982C>T
NC_000011.8:g.107686192C>T
NG_009830.1:g.92424C>T
NG_054724.1:g.164578G>A
ENST00000452508.7:c.5858C>T
ENST00000713593.1:c.*5329C>T
ENST00000278616.9:c.5858C>T
ENST00000525056.2:n.277C>T
ENST00000682286.1:n.615C>T
ENST00000682302.1:n.276C>T
ENST00000683174.1:n.7342C>T
ENST00000683524.1:n.1082C>T
ENST00000684152.1:n.1572C>T
ENST00000527805.6:c.*922C>T
ENST00000675595.1:c.*922C>T
ENST00000675843.1:c.5858C>T
ENST00000278616.8:c.5858C>T
ENST00000452508.6:c.5858C>T
ENST00000524792.5:n.2073C>T
ENST00000525729.5:c.641-1184G>A
ENST00000529588.5:c.282C>T
ENST00000532765.1:n.175C>T
ENST00000533690.5:n.1262C>T
NM_000051.3:c.5858C>T
NM_001330368.1:c.641-1184G>A
NM_001351110.1:c.*39-1184G>A
NM_001351834.1:c.5858C>T
NM_001330368.2:c.641-1184G>A
NM_001351110.2:c.*39-1184G>A
NM_001351834.2:c.5858C>T

Uncertain Significance

• Met criteria codes: PS3_Supporting PP3 PM3 PM2_Supporting

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 1.3.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.5858C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1953 (p.Thr1953Ile). This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 18634022, 26896183). This variant is absent from gnomAD v2.1.1. Additionally, experimental studies showed that this variant impacts ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_supporting, PS3_supporting, PP3)

Met criteria codes

• PS3_Supporting: Additionally ,Experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022)
• PP3: The computational predictor REVEL gives a score of 0.85, which is above the threshold of ≥.733, evidence that correlates with impact to ATM function.
• PM3: This variant has been detected in atleast 2 individuals with Ataxia-Telangiectasia(PMID:26896183,18634022)
• PM2_Supporting: This variant is absent from gnomAD v2.1.1.