NM_000051.4(ATM):c.6055T>C (p.Tyr2019His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 24, 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:: RCV001024843.13

Allele description [Variation Report for NM_000051.4(ATM):c.6055T>C (p.Tyr2019His)]

NM_000051.4(ATM):c.6055T>C (p.Tyr2019His)

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.6055T>C (p.Tyr2019His)

HGVS:

NC_000011.10:g.108315871T>C
NG_009830.1:g.98040T>C
NG_054724.1:g.158962A>G
NM_000051.4:c.6055T>CMANE SELECT
NM_001330368.2:c.641-6800A>G
NM_001351110.2:c.*39-6800A>G
NM_001351834.2:c.6055T>C
NP_000042.3:p.Tyr2019His
NP_000042.3:p.Tyr2019His
NP_001338763.1:p.Tyr2019His
LRG_135t1:c.6055T>C
LRG_135:g.98040T>C
LRG_135p1:p.Tyr2019His
NC_000011.9:g.108186598T>C
NC_000011.9:g.108186598T>C
NM_000051.3:c.6055T>C

Protein change:

Y2019H

Links:

dbSNP: rs1591776885

NCBI 1000 Genomes Browser:

rs1591776885

Molecular consequence:

NM_001330368.2:c.641-6800A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6800A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6055T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6055T>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

Recent activity

Clear Turn Off Turn On

Strategies to Reduce Harm Through Clinical Research - Advancing Clinical Researc...
Strategies to Reduce Harm Through Clinical Research - Advancing Clinical Research with Pregnant and Lactating Populations
Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-...
Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis - Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001186929	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 27, 2020)	germline	clinical testing	Citation Link,
SCV004361782	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30287823, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001186929

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 27, 2020)

germline

clinical testing

Citation Link,

SCV004361782

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 24, 2022)

germline

clinical testing

PubMed (2)
[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

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

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

Details of each submission

From Ambry Genetics, SCV001186929.4

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

Description

The p.Y2019H variant (also known as c.6055T>C), located in coding exon 40 of the ATM gene, results from a T to C substitution at nucleotide position 6055. The tyrosine at codon 2019 is replaced by histidine, an amino acid with similar properties. This alteration was reported in 1/7051 female Japanese breast cancer cases and not in 11241 controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). 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

From Color Diagnostics, LLC DBA Color Health, SCV004361782.1

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

Description

This missense variant replaces tyrosine with histidine at codon 2019 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 been reported in an individual affected with breast cancer (PMID: 30287823). This variant has not been identified 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: Oct 13, 2024

ClinVar

Relating variation to medicine