rs146531614

chr11-108271343-A-Gchr11-108271343-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):c.3014A>G(p.Asn1005Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,613,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1005H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:10 O:1
• Conservation: PhyloP100: -0.578

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051086843).
• BP6: Variant 11-108271343-A-G is Benign according to our data. Variant chr11-108271343-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127366.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=8, Likely_benign=5, not_provided=1}. Variant chr11-108271343-A-G is described in Lovd as [Benign]. Variant chr11-108271343-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3014A>G	p.Asn1005Ser	missense_variant	20/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3014A>G	p.Asn1005Ser	missense_variant	20/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251348 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000189 AC: 277 AN: 1461802 Hom.: 1 Cov.: 36 AF XY: 0.000183 AC XY: 133 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74330

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000514 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 06, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Benign and reported on 03-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2017	This variant is denoted ATM c.3014A>G at the cDNA level, p.Asn1005Ser (N1005S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been reported in individuals with personal histories of breast, ovarian, and pancreatic cancer (Grant 2015, Lu 2015, Tung 2016, Decker 2017). This variant was reported in a multiethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Asn1005Ser was observed at an allele frequency of 0.65% (66/10,142 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the beta-adaptin interaction domain (Tavtigian 2009). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn1005Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	ATM: BP1, BP4 -

Hereditary cancer-predisposing syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 17, 2014	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2021	Variant summary: ATM c.3014A>G (p.Asn1005Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 253746 control chromosomes (gnomAD and Weitzel_2019), predominantly in the Ashkenazi Jewish cohort at an allele frequency of 0.0065. This frequency is approximately 6.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in individuals of Ashkenazi Jewish origin. In addition, FLOSSIES (cohort of individuals older than 70 that never had cancer), this variant was also observed with an allele frequency of 0.0004047 (4/9884 individuals). c.3014A>G has been reported in the literature in individuals affected with breast cancer, ovarian cancer and in individuals with an increased risk of pancreatic cancer (Tung_2016, Lu _2015, Abe_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ATM NM_000051.3 exon 20 p.Asn1005Ser (c.3014A>G): This variant has been reported in the literature as germline in at least 3 individuals with cancer (Haiman 2013 PMID:23555315, Lu 2015 PMID:26689913, Tung 2016 PMID:26976419). This variant is present in 0.6% (65/10362) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108142070-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several conflicting interpretations between Variant of Uncertain Significance (VUS) and Likely Benign/Benign (Variation ID:127366). This variant amino acid Serine (Ser) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 23, 2023

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Asn1005Ser variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung 2016). The variant was also identified in dbSNP (ID: rs146531614) as “With Uncertain significance allele”, ClinVar (classified as benign by Ambry Genetics; as likely benign by Invitae; as uncertain significance by GeneDx and 5 clinical laboratories), Clinvitae, MutDB, and LOVD 3.0 databases. The variant was not identified in the COGR, or the Cosmic database. The variant was identified in control databases in 100 of 277096 chromosomes at a frequency of 0.0004 variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24030 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 17 of 34418 chromosomes (freq: 0.001), European in 13 of 126614 chromosomes (freq: 0.0001), Ashkenazi Jewish in 66 of 10142 chromosomes (freq: 0.01); it was not observed in the East Asian, Finnish, and South Asian populations. The p.Asn1005 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Aug 30, 2022

The ATM c.3014A>G (p.Asn1005Ser) missense change has a maximum subpopulation frequency of 0.048% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast cancer (PMID: 26976419). This variant has been reported in 4 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

ATM-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.057
Dann	Benign	0.32
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.60	T;T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.099
Sift	Benign	0.78	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.084, 0.13
MVP		0.56
MPC		0.097
ClinPred		0.0069	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.029

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146531614; hg19: chr11-108142070;