NM_000051.4(ATM):c.2414G>A (p.Arg805Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 11, 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:: RCV000130968.12

Allele description [Variation Report for NM_000051.4(ATM):c.2414G>A (p.Arg805Gln)]

NM_000051.4(ATM):c.2414G>A (p.Arg805Gln)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.2414G>A (p.Arg805Gln)

HGVS:

NC_000011.10:g.108259023G>A
NG_009830.1:g.41192G>A
NM_000051.4:c.2414G>AMANE SELECT
NM_001351834.2:c.2414G>A
NP_000042.3:p.Arg805Gln
NP_000042.3:p.Arg805Gln
NP_001338763.1:p.Arg805Gln
LRG_135t1:c.2414G>A
LRG_135:g.41192G>A
LRG_135p1:p.Arg805Gln
NC_000011.9:g.108129750G>A
NM_000051.3:c.2414G>A
p.R805Q

Protein change:

R805Q

Links:

dbSNP: rs587782255

NCBI 1000 Genomes Browser:

rs587782255

Molecular consequence:

NM_000051.4:c.2414G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.2414G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000185883	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jul 20, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19781682, 25186627, 28652578, 33436325 Citation Link,
SCV000903406	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17393301, 19781682, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185883

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jul 20, 2022)

germline

clinical testing

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

Citation Link,

SCV000903406

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 11, 2023)

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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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

Rare germline variants in ATM are associated with chronic lymphocytic leukemia.

Tiao G, Improgo MR, Kasar S, Poh W, Kamburov A, Landau DA, Tausch E, Taylor-Weiner A, Cibulskis C, Bahl S, Fernandes SM, Hoang K, Rheinbay E, Kim HT, Bahlo J, Robrecht S, Fischer K, Hallek M, Gabriel S, Lander ES, Stilgenbauer S, Wu CJ, et al.

Leukemia. 2017 Oct;31(10):2244-2247. doi: 10.1038/leu.2017.201. Epub 2017 Jun 27. No abstract available.

PubMed [citation]

PMID:: 28652578
PMCID:: PMC5628120

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000185883.7

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

Description

The p.R805Q variant (also known as c.2414G>A), located in coding exon 15 of the ATM gene, results from a G to A substitution at nucleotide position 2414. The arginine at codon 805 is replaced by glutamine, an amino acid with highly similar properties. This variant has been previously detected in breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Tung N et al. Cancer, 2015 Jan;121:25-33). This variant has also been reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This alteration has been reported in the germline of 1 of 8,920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000903406.4

#	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 arginine with glutamine at codon 805 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 4/53457 controls (PMID: 33471991). This variant has been reported in several individuals affected with breast cancer (PMID: 17393301, 19781682). This variant has been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic BRCA1 variant (Color internal data). This variant has been identified in 7/251236 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: Apr 6, 2024

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