NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter) AND Familial cancer of breast

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001250440.17

Allele description [Variation Report for NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter)]

NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter)

HGVS:

NC_000011.10:g.108330233C>T
NG_009830.1:g.112402C>T
NG_054724.1:g.144600G>A
NM_000051.4:c.7327C>TMANE SELECT
NM_001330368.2:c.641-21162G>A
NM_001351110.2:c.*38+4987G>A
NM_001351834.2:c.7327C>T
NP_000042.3:p.Arg2443Ter
NP_000042.3:p.Arg2443Ter
NP_001338763.1:p.Arg2443Ter
LRG_135t1:c.7327C>T
LRG_135:g.112402C>T
LRG_135p1:p.Arg2443Ter
NC_000011.9:g.108200960C>T
NM_000051.3:c.7327C>T
NM_001351834.2:c.7327C>T

Protein change:

R2443*; ARG2443TER

Links:

OMIM: 607585.0019; dbSNP: rs121434220

NCBI 1000 Genomes Browser:

rs121434220

Molecular consequence:

NM_001330368.2:c.641-21162G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+4987G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7327C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.7327C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001424815	Division of Medical Genetics, University of Washington - CSER_CHARM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 15, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001499653	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003921051	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004206287	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 11, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004932919	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jan 31, 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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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 Division of Medical Genetics, University of Washington - CSER_CHARM, SCV001424815.1

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

Description

The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Molecular Diagnostics, Institute of Oncology Ljubljana, SCV001499653.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV003921051.4

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

Description

Criteria applied: PVS1,PM2_SUP,PM3_SUP

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

From Baylor Genetics, SCV004206287.2

#	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 Myriad Genetics, Inc., SCV004932919.1

#	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 termination codon and is 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: Nov 3, 2024

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