NM_000051.4(ATM):c.8147T>C (p.Val2716Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 3, 2023
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:: RCV000132066.30

Allele description [Variation Report for NM_000051.4(ATM):c.8147T>C (p.Val2716Ala)]

NM_000051.4(ATM):c.8147T>C (p.Val2716Ala)

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.8147T>C (p.Val2716Ala)

Other names:

p.V2716A:GTT>GCT

HGVS:

NC_000011.10:g.108335105T>C
NG_009830.1:g.117274T>C
NG_054724.1:g.139728A>G
NM_000051.4:c.8147T>CMANE SELECT
NM_001330368.2:c.641-26034A>G
NM_001351110.2:c.*38+115A>G
NM_001351834.2:c.8147T>C
NP_000042.3:p.Val2716Ala
NP_000042.3:p.Val2716Ala
NP_000042.3:p.Val2716Ala
NP_001338763.1:p.Val2716Ala
LRG_135t1:c.8147T>C
LRG_135:g.117274T>C
LRG_135p1:p.Val2716Ala
NC_000011.9:g.108205832T>C
NM_000051.3:c.8147T>C
p.V2716A

Protein change:

V2716A

Links:

dbSNP: rs587782652

NCBI 1000 Genomes Browser:

rs587782652

Molecular consequence:

NM_001330368.2:c.641-26034A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+115A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8147T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.8147T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187129	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 12, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 11805335, 19535770, 21354641, 21792198, 21965147, 22146522, 25122203, 25957637, 29478780, 29909963, 30322717, 30549301, 30579816, 30819809, 31050087, 32875559, 34445196 Citation Link,
SCV000682458	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 11805335, 16864838, 19535770, 21354641, 21965147, 25957637, 26681312, 26976419, 30819809, 31050087, 32854451, 33471991, 25741868
SCV000992207	Academic Department of Medical Genetics, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002527130	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Sep 10, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 26681312, 32854451, 28843361, 29478780, 30549301, 11805335, 21792198 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia.

Byrd PJ, Srinivasan V, Last JI, Smith A, Biggs P, Carney EF, Exley A, Abson C, Stewart GS, Izatt L, Taylor AM.

Br J Cancer. 2012 Jan 17;106(2):262-8. doi: 10.1038/bjc.2011.534. Epub 2011 Dec 6.

PubMed [citation]

PMID:: 22146522
PMCID:: PMC3261689

The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.

Méneret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E, Tranchant C, Rivaud-Péchoux S, Degos B, Benyahia B, Suarez F, Maisonobe T, Koenig M, Durr A, Stern MH, Dubois d'Enghien C, Fischer A, Vidailhet M, Stoppa-Lyonnet D, Grabli D, Anheim M.

Neurology. 2014 Sep 16;83(12):1087-95. doi: 10.1212/WNL.0000000000000794. Epub 2014 Aug 13.

PubMed [citation]

PMID:: 25122203

See all PubMed Citations (24)

Details of each submission

From Ambry Genetics, SCV000187129.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The p.V2716A variant (also known as c.8147T>C), located in coding exon 54 of the ATM gene, results from a T to C substitution at nucleotide position 8147. The valine at codon 2716 is replaced by alanine, an amino acid with similar properties. This alteration has been reported together with second known pathogenic ATM mutations in multiple individuals with milder, "variant ataxia-telangiectasia" (Verhagen MM et al. Neurology. 2009 Aug;73:430-7; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Méneret A, Neurology. 2014 Sep;83:1087-95; Lohmann E et al. J. Neurol. 2015 Jul;262:1724-7; van Os NJH et al. J. Med. Genet., 2019 May;56:308-316; Galatolo D et al. Int J Mol Sci, 2021 Aug;22:). Additionally, this alteration was reported in three unrelated women with ataxia-telangiectasia and breast cancer (Mandigers C et al. Radiother Oncol. 2011 Apr;99:97-8; Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel) 2020 Aug;12(9)). This alteration was also identified in an individual diagnosed with prostate cancer (Wokoorczyk D et al. Int J Cancer, 2020 Nov;147:2793-2800). This alteration has been associated with reduced ATM protein expression, decreased ATM kinase activity, and increased radiosensitivity in studies using A-T lymphoblastoid cell lines (Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Scott SP et al. Proc. Natl. Acad. Sci. U.S.A. 2002 Jan;99:925-30). Another alteration at the same codon, p.V2716F (c.8146G>T), has been detected in an individual with a clinical diagnosis of ataxia telangiectasia (Hersby DS et al. J Pediatr Hematol Oncol. 2015 Mar;37(2):154-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000682458.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces valine with alanine at codon 2716 of the kinase domain of ATM protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the variant results in the loss of ATM kinase activity and increased radiosensitivity (PMID: 11805335). This variant has been reported in many individuals affected with breast cancer (PMID: 26681312, 26976419, 32854451, 33471991). In a large international case-control study, this variant was reported in 16/60466 breast cancer cases and 6/53461 controls (OR=2.358, 95%CI 0.923 to 6.027, p-value=0.086; PMID: 33471991). This variant has been reported in individuals affected with classic ataxia telangiectasia (PMID: 31050087) and atypical, late-onset ataxia telangiectasia (PMID: 25957637, 16864838, 21354641, 19535770, 21965147, 30819809). This variant has been identified in 9/282750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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 Academic Department of Medical Genetics, University of Cambridge, SCV000992207.1

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

Description

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

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

From Sema4, Sema4, SCV002527130.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

#	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

Last Updated: Nov 3, 2024

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