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NM_000051.4(ATM):c.7816A>G (p.Ile2606Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 31, 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:
RCV000166765.19

Allele description [Variation Report for NM_000051.4(ATM):c.7816A>G (p.Ile2606Val)]

NM_000051.4(ATM):c.7816A>G (p.Ile2606Val)

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.7816A>G (p.Ile2606Val)
HGVS:
  • NC_000011.10:g.108332789A>G
  • NG_009830.1:g.114958A>G
  • NG_054724.1:g.142044T>C
  • NM_000051.4:c.7816A>GMANE SELECT
  • NM_001330368.2:c.641-23718T>C
  • NM_001351110.2:c.*38+2431T>C
  • NM_001351834.2:c.7816A>G
  • NP_000042.3:p.Ile2606Val
  • NP_000042.3:p.Ile2606Val
  • NP_001338763.1:p.Ile2606Val
  • LRG_135t1:c.7816A>G
  • LRG_135:g.114958A>G
  • LRG_135p1:p.Ile2606Val
  • NC_000011.9:g.108203516A>G
  • NM_000051.3:c.7816A>G
  • p.I2606V
Protein change:
I2606V
Links:
dbSNP: rs376824528
NCBI 1000 Genomes Browser:
rs376824528
Molecular consequence:
  • NM_001330368.2:c.641-23718T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.*38+2431T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.4:c.7816A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.7816A>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000217578Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Oct 31, 2023) 		germlineclinical testing

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

Citation Link,

SCV000902970Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 21, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Frequency of germline genetic variants in women with a personal or family history of breast cancer from Brazil.

Pereira JZ, Carneiro JG, Vieira MS, Valente BM, de Oliveira PZ, Mello CL, de Campos CLV, Gomes KB.

Mol Biol Rep. 2022 Oct;49(10):9509-9520. doi: 10.1007/s11033-022-07840-0. Epub 2022 Aug 18.

PubMed [citation]
PMID:
35980532

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 (6)

Details of each submission

From Ambry Genetics, SCV000217578.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The p.I2606V variant (also known as c.7816A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7816. The isoleucine at codon 2606 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals with a personal and/or family history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000902970.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This missense variant replaces isoleucine with valine at codon 2606 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). RNA studies have showed this variant causes a minor increase in exon 53 skipping (PMID: 35806449). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 35806449), ovarian cancer (PMID: 36531003), or prostate cancer (PMID: 33436325). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054, p-value=1; PMID: 33471991). This variant has also been identified in 4/250604 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024