VCV000127372.24 - ClinVar

NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

Interpretation:: Conflicting interpretations of pathogenicity
Uncertain significance(3); Likely benign(5)
Review status:: criteria provided, conflicting interpretations
Submissions:: 9
First in ClinVar:: Jul 24, 2016
Most recent Submission:: Nov 29, 2022
Last evaluated:: May 27, 2022
Accession:: VCV000127372.24
Variation ID:: 127372
Description:: single nucleotide variant

NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

Allele ID

132829

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

11q22.3

Genomic location

11: 108281041 (GRCh38) GRCh38 UCSC

11: 108151768 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.3449G>C MANE Select	NP_000042.3:p.Arg1150Thr	missense
NM_001351834.2:c.3449G>C	NP_001338763.1:p.Arg1150Thr	missense
NC_000011.10:g.108281041G>C
NC_000011.9:g.108151768G>C
NG_009830.1:g.63210G>C
LRG_135:g.63210G>C
LRG_135t1:c.3449G>C	LRG_135p1:p.Arg1150Thr

... more HGVS ... less HGVS

Protein change

R1150T

Other names

p.R1150T:AGA>ACA

Canonical SPDI

NC_000011.10:108281040:G:C

Functional consequence

Global minor allele frequency (GMAF)

0.00060 (C)

Allele frequency

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00018

Exome Aggregation Consortium (ExAC) 0.00019

1000 Genomes Project 0.00060

Links

ClinGen: CA286809

dbSNP: rs555219189

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not provided	Uncertain significance	2	criteria provided, multiple submitters, no conflicts	Apr 8, 2021	RCV000115177.7
Hereditary cancer-predisposing syndrome	Likely benign	3	criteria provided, multiple submitters, no conflicts	Dec 5, 2021	RCV000215488.10
Ataxia-telangiectasia syndrome	Likely benign	2	criteria provided, single submitter	Dec 13, 2021	RCV000199179.13
not specified	Conflicting interpretations of pathogenicity	2	criteria provided, conflicting interpretations	May 27, 2022	RCV001818259.4

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
ATM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	8326	13383

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Uncertain significance (Mar 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories,Mayo Clinic Accession: SCV001714396.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (Apr 08, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149086.13 First in ClinVar: May 17, 2014 Last updated: Jul 24, 2016	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Singh 2018); … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Singh 2018); This variant is associated with the following publications: (PMID: 29470806, 31919090) (less)
Uncertain significance (Mar 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory,University of Chicago Accession: SCV002068402.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Dec 13, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV000254084.9 First in ClinVar: Oct 11, 2015 Last updated: May 16, 2022	Publications: PubMed (1) PubMed: 28492532
Likely benign (Dec 05, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4,Sema4 Accession: SCV002536023.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Publications: PubMed (3) PubMed: 29470806‚ 33552952‚ 33471991
Likely benign (May 27, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002548067.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Publications: PubMed (1) PubMed: 29470806 Comment: Variant summary: ATM c.3449G>C (p.Arg1150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: ATM c.3449G>C (p.Arg1150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251216 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM (0.001) causing an ATM-related Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3449G>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers to include breast cancer (example, Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Likely benign (Apr 20, 2021)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000278041.6 First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022	Publications: PubMed (4) PubMed: 28580595‚ 29470806‚ 31742824‚ 33471991 Comment: This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more) This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Number of individuals with the variant: 1
Likely benign (Oct 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000687480.4 First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457147.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Singh 2018); This variant is associated with the following publications: (PMID: 29470806, 31919090)

Comment:

Variant summary: ATM c.3449G>C (p.Arg1150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251216 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM (0.001) causing an ATM-related Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3449G>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers to include breast cancer (example, Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening.	Kadri MSN	Frontiers in oncology	2021	PMID: 33552952
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals.	Shao D	Cancer science	2020	PMID: 31742824
Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.	Singh J	Breast cancer research and treatment	2018	PMID: 29470806
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients.	Xie Y	Clinical genetics	2018	PMID: 28580595
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.	Nykamp K	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492532

Text-mined citations for rs555219189...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 29, 2022

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs555219189...