NM_000051.4(ATM):c.1443A>C (p.Leu481Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 20, 2021
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:: RCV000575362.5

Allele description [Variation Report for NM_000051.4(ATM):c.1443A>C (p.Leu481Phe)]

NM_000051.4(ATM):c.1443A>C (p.Leu481Phe)

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.1443A>C (p.Leu481Phe)

HGVS:

NC_000011.10:g.108250908A>C
NG_009830.1:g.33077A>C
NM_000051.4:c.1443A>CMANE SELECT
NM_001351834.2:c.1443A>C
NP_000042.3:p.Leu481Phe
NP_000042.3:p.Leu481Phe
NP_001338763.1:p.Leu481Phe
LRG_135t1:c.1443A>C
LRG_135:g.33077A>C
LRG_135p1:p.Leu481Phe
NC_000011.9:g.108121635A>C
NM_000051.3:c.1443A>C

Protein change:

L481F

Links:

dbSNP: rs753808755

NCBI 1000 Genomes Browser:

rs753808755

Molecular consequence:

NM_000051.4:c.1443A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.1443A>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
SCV000665658	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 20, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19638463, 28779002 Citation Link,
SCV001342224	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000665658

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 20, 2021)

germline

clinical testing

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

Citation Link,

SCV001342224

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 14, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sequence variant discovery in DNA repair genes from radiosensitive and radiotolerant prostate brachytherapy patients.

Pugh TJ, Keyes M, Barclay L, Delaney A, Krzywinski M, Thomas D, Novik K, Yang C, Agranovich A, McKenzie M, Morris WJ, Olive PL, Marra MA, Moore RA.

Clin Cancer Res. 2009 Aug 1;15(15):5008-16. doi: 10.1158/1078-0432.CCR-08-3357. Epub 2009 Jul 28.

PubMed [citation]

PMID:: 19638463

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, Easton DF.

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

PubMed [citation]

PMID:: 28779002
PMCID:: PMC5740532

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000665658.5

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

Description

The p.L481F variant (also known as c.1443A>C), located in coding exon 9 of the ATM gene, results from an A to C substitution at nucleotide position 1443. The leucine at codon 481 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with prostate cancer (Pugh TJ et al. Clin Cancer Res, 2009 Aug;15:5008-16). Additionally, this alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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, SCV001342224.1

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

#	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: May 1, 2024

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