NM_000051.4(ATM):c.7271T>G (p.Val2424Gly) AND Familial cancer of breast

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 9, 2022
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:: RCV000709707.17

Allele description [Variation Report for NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)]

NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)

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.7271T>G (p.Val2424Gly)

Other names:

p.V2424G:GTA>GGA; NM_000051.3(ATM):c.7271T>G

HGVS:

NC_000011.10:g.108329202T>G
NG_009830.1:g.111371T>G
NG_054724.1:g.145631A>C
NM_000051.4:c.7271T>GMANE SELECT
NM_001330368.2:c.641-20131A>C
NM_001351110.2:c.*38+6018A>C
NM_001351834.2:c.7271T>G
NP_000042.3:p.Val2424Gly
NP_000042.3:p.Val2424Gly
NP_001338763.1:p.Val2424Gly
LRG_135t1:c.7271T>G
LRG_135:g.111371T>G
LRG_135p1:p.Val2424Gly
NC_000011.9:g.108199929T>G
NM_000051.3:c.7271T>G
Q13315:p.Val2424Gly
p.V2424G

Protein change:

V2424G; VAL2424GLY

Links:

UniProtKB: Q13315#VAR_010854; OMIM: 607585.0005; dbSNP: rs28904921

NCBI 1000 Genomes Browser:

rs28904921

Molecular consequence:

NM_001330368.2:c.641-20131A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+6018A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7271T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7271T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial
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
SCV000839881	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002499282	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen hbop acmg specifications atm v1-1)	Pathogenic (Mar 9, 2022)	germline	curation	Citation Link,
SCV002761739	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003798999	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004203716	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, 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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839881.1

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

Description

This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/11-108199929-T-G). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant.

#	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 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV002499282.1

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

Description

The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI greater than or equal to 1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761739.1

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003798999.2

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

Description

PP3, PS3_Moderate, PS4, PM3_Very strong, PP1

#	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 Baylor Genetics, SCV004203716.1

#	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

Last Updated: Apr 15, 2024

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