NM_000051.4(ATM):c.1355del (p.Thr452fs) AND Familial cancer of breast

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003467128.3

Allele description [Variation Report for NM_000051.4(ATM):c.1355del (p.Thr452fs)]

NM_000051.4(ATM):c.1355del (p.Thr452fs)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.1355del (p.Thr452fs)

Other names:

NM_000051.4(ATM):c.1355del; p.Thr452fs

HGVS:

NC_000011.10:g.108250820del
NG_009830.1:g.32989del
NM_000051.4:c.1355delMANE SELECT
NM_001351834.2:c.1355del
NP_000042.3:p.Thr452fs
NP_000042.3:p.Thr452fs
NP_001338763.1:p.Thr452fs
LRG_135t1:c.1355del
LRG_135:g.32989del
LRG_135p1:p.Thr452fs
NC_000011.9:g.108121547del
NM_000051.3:c.1355del
NM_000051.3:c.1355delC
p.T452NFS*21

Protein change:

T452fs

Links:

dbSNP: rs587781776

NCBI 1000 Genomes Browser:

rs587781776

Molecular consequence:

NM_000051.4:c.1355del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.1355del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: BREAST CANCER, FAMILIAL; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004209491	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004565380	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HBOP ACMG Specifications ATM V1.2.0)	Pathogenic (Jan 25, 2024)	germline	curation	Citation Link,
SCV004930361	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jan 16, 2024)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004209491

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 7, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004565380

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen HBOP ACMG Specifications ATM V1.2.0)

Pathogenic
(Jan 25, 2024)

germline

curation

Citation Link,

SCV004930361

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Jan 16, 2024)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Baylor Genetics, SCV004209491.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV004565380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1355del (p.Thr452AsnfsTer21) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 9463314, 10234507, 26896183). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Supporting, PM2_Supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004930361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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