NM_000051.4(ATM):c.6226A>G (p.Ile2076Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 1, 2022
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:: RCV000217659.17

Allele description [Variation Report for NM_000051.4(ATM):c.6226A>G (p.Ile2076Val)]

NM_000051.4(ATM):c.6226A>G (p.Ile2076Val)

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.6226A>G (p.Ile2076Val)

HGVS:

NC_000011.10:g.108317400A>G
NG_009830.1:g.99569A>G
NG_054724.1:g.157433T>C
NM_000051.4:c.6226A>GMANE SELECT
NM_001330368.2:c.641-8329T>C
NM_001351110.2:c.*39-8329T>C
NM_001351834.2:c.6226A>G
NP_000042.3:p.Ile2076Val
NP_000042.3:p.Ile2076Val
NP_001338763.1:p.Ile2076Val
LRG_135t1:c.6226A>G
LRG_135:g.99569A>G
LRG_135p1:p.Ile2076Val
NC_000011.9:g.108188127A>G
NM_000051.3:c.6226A>G

Protein change:

I2076V

Links:

dbSNP: rs755973863

NCBI 1000 Genomes Browser:

rs755973863

Molecular consequence:

NM_001330368.2:c.641-8329T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-8329T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6226A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6226A>G - 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
SCV000278591	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16832357, 34299313 Citation Link,
SCV000903405	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 15, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 28135145, 34299313, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278591

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000903405

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 15, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D; Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR, Rahman N.

Nat Genet. 2006 Aug;38(8):873-5. Epub 2006 Jul 9.

PubMed [citation]

PMID:: 16832357

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000278591.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.I2076V variant (also known as c.6226A>G), located in coding exon 42 of the ATM gene, results from an A to G substitution at nucleotide position 6226. The isoleucine at codon 2076 is replaced by valine, an amino acid with highly similar properties. In a large study of familial breast cancer families, this variant was identified in 1/443 cases and 0/521 controls (Renwick A et al. Nat. Genet., 2006 Aug;38:873-5). This alteration was also identified in an individual diagnosed with breast cancer (Guglielmi C et al. Int J Mol Sci, 2021 Jul;22:). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV000903405.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces isoleucine with valine at codon 2076 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and colorectal cancer (PMID: 25186627, 28135145, 34299313). This variant has been identified in 3/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 30, 2024

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