NM_000051.4(ATM):c.7867C>A (p.Leu2623Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 21, 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:: RCV001180350.13

Allele description [Variation Report for NM_000051.4(ATM):c.7867C>A (p.Leu2623Ile)]

NM_000051.4(ATM):c.7867C>A (p.Leu2623Ile)

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.7867C>A (p.Leu2623Ile)

HGVS:

NC_000011.10:g.108332840C>A
NG_009830.1:g.115009C>A
NG_054724.1:g.141993G>T
NM_000051.4:c.7867C>AMANE SELECT
NM_001330368.2:c.641-23769G>T
NM_001351110.2:c.*38+2380G>T
NM_001351834.2:c.7867C>A
NP_000042.3:p.Leu2623Ile
NP_000042.3:p.Leu2623Ile
NP_001338763.1:p.Leu2623Ile
LRG_135t1:c.7867C>A
LRG_135:g.115009C>A
LRG_135p1:p.Leu2623Ile
NC_000011.9:g.108203567C>A
NC_000011.9:g.108203567C>A
NM_000051.3:c.7867C>A

Protein change:

L2623I

Links:

dbSNP: rs774118570

NCBI 1000 Genomes Browser:

rs774118570

Molecular consequence:

NM_001330368.2:c.641-23769G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+2380G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7867C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7867C>A - 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

Recent activity

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transcription elongation factor A protein-like 4 isoform 1 [Homo sapiens]
transcription elongation factor A protein-like 4 isoform 1 [Homo sapiens]
gi|55749442|ref|NP_001006936.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001345262	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003866520	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001345262

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 13, 2022)

germline

clinical testing

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

SCV003866520

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 21, 2022)

germline

clinical testing

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

Citation Link

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Multigene testing of moderate-risk genes: be mindful of the missense.

Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, et al.

J Med Genet. 2016 Jun;53(6):366-76. doi: 10.1136/jmedgenet-2015-103398. Epub 2016 Jan 19.

PubMed [citation]

PMID:: 26787654
PMCID:: PMC4893078

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001345262.2

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

Description

This missense variant replaces leucine with isoleucine at codon 2623 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250852 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

From Ambry Genetics, SCV003866520.2

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

Description

The p.L2623I variant (also known as c.7867C>A), located in coding exon 52 of the ATM gene, results from a C to A substitution at nucleotide position 7867. The leucine at codon 2623 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J Med Genet, 2016 06;53:366-76). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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