Variant: NM_000051.4(ATM):c.5821G>C (p.Val1941Leu)

CA286904

127412 (ClinVar)

Gene: ATM

Condition: ATM-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 78fa8022-107a-46ce-b1f1-2850f55f1a81

Approved on: 2025-06-11

Published on: 2025-07-10

HGVS expressions

NM_000051.4:c.5821G>C
NM_000051.4(ATM):c.5821G>C (p.Val1941Leu)
NC_000011.10:g.108310218G>C
CM000673.2:g.108310218G>C
NC_000011.9:g.108180945G>C
CM000673.1:g.108180945G>C
NC_000011.8:g.107686155G>C
NG_009830.1:g.92387G>C
NG_054724.1:g.164615C>G
ENST00000452508.7:c.5821G>C
ENST00000713593.1:c.*5292G>C
ENST00000278616.9:c.5821G>C
ENST00000525056.2:n.240G>C
ENST00000682286.1:n.578G>C
ENST00000682302.1:n.239G>C
ENST00000683174.1:n.7305G>C
ENST00000683524.1:n.1045G>C
ENST00000684152.1:n.1535G>C
ENST00000527805.6:c.*885G>C
ENST00000675595.1:c.*885G>C
ENST00000675843.1:c.5821G>C
ENST00000278616.8:c.5821G>C
ENST00000452508.6:c.5821G>C
ENST00000524792.5:n.2036G>C
ENST00000525729.5:c.641-1147C>G
ENST00000529588.5:c.245G>C
ENST00000532765.1:n.138G>C
ENST00000533690.5:n.1225G>C
NM_000051.3:c.5821G>C
NM_001330368.1:c.641-1147C>G
NM_001351110.1:c.*39-1147C>G
NM_001351834.1:c.5821G>C
NM_001330368.2:c.641-1147C>G
NM_001351110.2:c.*39-1147C>G
NM_001351834.2:c.5821G>C

Likely Benign

• Met criteria codes: BP2_Strong PS3

• Not Met criteria codes: BS1 BP4 PP3 PM2

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.5821G>C (p.Val1941Leu) variant in ATM is a missense variant predicted to cause substitution of valine by leucine at amino acid 1941 (p.Val1941Leu). This variant has been observed in the homozygous state or phase unknown with a pathogenic variant in multiple individuals without Ataxia-Telangiectasia (Invitae internal data). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0003843 the Remaining population (PM2_Supporting, BS1, and BA1 are not met). ATM kinase activity assay in ATM-null lymphoblastoid cell line showed reduced kinase activity of ATM and its downstream targets indicating that this variant may impact protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.548, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets criteria to be classified as likely benign 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. (BP2_Strong, PS3_Supporting)

Met criteria codes

• BP2_Strong: This variant has been observed in a homozygous state or phase unknown with a pathogenic variant in ATM in multiple individuals without Ataxia-Telangiectasia (Invitae, BP2_strong) (-26 pts)
• PS3: ATM kinase activity assay in ATM-null lymphoblastoid cell line showed reduced kinase activity of ATM and its downstream targets indicating that this variant impacts protein function (PMID:19431188) (PS3_Supporting).

Not Met criteria codes

• BS1: The filtering allele frequency is 0.01818% for non-Finish European chromosomes by gnomAD v2.1.1, which is lower than the ClinGen HBOP VCEP threshold (>0.05%) for BS1, and therefore does not meet this criterion. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002482 (32/128930 alleles) in European (non-Finnish) population (PM2_supporting not met, BS1 not met).
• BP4: The computational predictor REVEL gives a score of 0.548, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function (PP3, BP4 not met).
• PP3: The computational predictor REVEL gives a score of 0.548, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function (PP3, BP4 not met).
• PM2: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002482 (32/128930 alleles) in European (non-Finnish) population (PM2_supporting not met, BS1 not met).