NM_000051.4(ATM):c.1814A>G (p.His605Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 15, 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:: RCV001013284.6

Allele description [Variation Report for NM_000051.4(ATM):c.1814A>G (p.His605Arg)]

NM_000051.4(ATM):c.1814A>G (p.His605Arg)

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.1814A>G (p.His605Arg)

HGVS:

NC_000011.10:g.108252828A>G
NG_009830.1:g.34997A>G
NM_000051.4:c.1814A>GMANE SELECT
NM_001351834.2:c.1814A>G
NP_000042.3:p.His605Arg
NP_000042.3:p.His605Arg
NP_001338763.1:p.His605Arg
LRG_135t1:c.1814A>G
LRG_135:g.34997A>G
LRG_135p1:p.His605Arg
NC_000011.9:g.108123555A>G
NM_000051.3:c.1814A>G

Protein change:

H605R

Links:

dbSNP: rs771877351

NCBI 1000 Genomes Browser:

rs771877351

Molecular consequence:

NM_000051.4:c.1814A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.1814A>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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PREDICTED: LOW QUALITY PROTEIN: ankyrin repeat-containing protein At3g12360-like...
PREDICTED: LOW QUALITY PROTEIN: ankyrin repeat-containing protein At3g12360-like [Cucumis melo]
gi|659067657|ref|XP_008440605.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001173852	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 15, 2022)	germline	clinical testing	Citation Link,
SCV004359777	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 6, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16914028, 20305132, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001173852

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 15, 2022)

germline

clinical testing

Citation Link,

SCV004359777

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 6, 2021)

germline

clinical testing

PubMed (3)
[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 variants and cancer risk in breast cancer patients from Southern Finland.

Tommiska J, Jansen L, Kilpivaara O, Edvardsen H, Kristensen V, Tamminen A, Aittomäki K, Blomqvist C, Børresen-Dale AL, Nevanlinna H.

BMC Cancer. 2006 Aug 16;6:209.

PubMed [citation]

PMID:: 16914028
PMCID:: PMC1592307

Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.

Bernstein JL, Haile RW, Stovall M, Boice JD Jr, Shore RE, Langholz B, Thomas DC, Bernstein L, Lynch CF, Olsen JH, Malone KE, Mellemkjaer L, Borresen-Dale AL, Rosenstein BS, Teraoka SN, Diep AT, Smith SA, Capanu M, Reiner AS, Liang X, Gatti RA, Concannon P; et al.

J Natl Cancer Inst. 2010 Apr 7;102(7):475-83. doi: 10.1093/jnci/djq055. Epub 2010 Mar 19.

PubMed [citation]

PMID:: 20305132
PMCID:: PMC2902825

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001173852.4

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

Description

The c.1814A>G (p.H605R) alteration is located in exon 12 (coding exon 11) of the ATM gene. This alteration results from a A to G substitution at nucleotide position 1814, causing the histidine (H) at amino acid position 605 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, 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, SCV004359777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces histidine with arginine at codon 605 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 cancer (PMID: 16914028, 20305132). However, in one study, this variant was not found in first- and second-degree relatives affected with breast cancer (PMID: 16914028). This variant has been identified in 4/281872 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: Sep 29, 2024

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