rs146382972

chr11-108235672-G-Achr11-108235672-G-Cchr11-108235672-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000051.4(ATM):c.334G>A(p.Ala112Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000146 in 1,604,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. A112V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 5.35

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016045034).
• BP6: Variant 11-108235672-G-A is Benign according to our data. Variant chr11-108235672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127370.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=4, Uncertain_significance=5}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000722 (110/152254) while in subpopulation AFR AF= 0.00248 (103/41552). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.334G>A	p.Ala112Thr	missense_variant, splice_region_variant	5/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.334G>A	p.Ala112Thr	missense_variant, splice_region_variant	5/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 250218 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135384

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000861 AC: 125 AN: 1452478 Hom.: 0 Cov.: 30 AF XY: 0.0000678 AC XY: 49 AN XY: 723078

Gnomad4 AFR exome AF: 0.00280

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74432

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000865

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2020	This variant is associated with the following publications: (PMID: 25318351, 25980754, 17333338, 27443514, 27720647, 19781682, 28779002, 23555315, 33095795) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2019	This alteration is classified as likely 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2023	Variant summary: ATM c.334G>A (p.Ala112Thr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 250408 control chromosomes (gnomAD, Hirsch_2008), predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 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 populations of African or African-American origin. The variant has also been found in 13/2559 (carrier freq=0.00508) African American women over the age of 70 without history of cancer (FLOSSIES dataset). c.334G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome, endometrial carcinoma, cerebellar ataxia, primary ovarian insufficiency and PDAC (examples: Tung_2014, Yurgelun_2015, Ring_2016, Coutelier_2018, Mullins_2019, Weitzel_2019, Franca_2020, Zimmermann_2021), but it was also reported in healthy controls (examples: Hirsch_2008, Weitzel_2019). 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 ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

ATM-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 01, 2024

The ATM c.334G>A variant is predicted to result in the amino acid substitution p.Ala112Thr. This variant has been reported in two individuals with breast cancer (Tung et al. 2014. PubMed ID: 25186627; Mullins and Gupta. 2019. PubMed ID: 31719806), in an individual with endometrial cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2), an individual with primary ovarian insufficiency (França et al. 2020. PubMed ID: 33095795), and in at least two individuals undergoing Lynch syndrome genetic testing (Yorczyk et al. 2014. PubMed ID: 25318351, Table 2; Yurgelun et al. 2015. PubMed ID: 25980754, Table S2). It has also been reported in controls from breast cancer cohort studies (Hirsch et al. 2007. PubMed ID: 17333338; Tavtigian et al. 2009. PubMed ID: 19781682. Table S2). This variant is reported in 0.27% of alleles in individuals of African descent in gnomAD, which is significantly more common than other known disease-causing ATM variants. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127370/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Ala112Thr variant was identified in 4 of 17948 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was present in 2 of 4988 control chromosomes (frequency: 0.0004) from healthy individuals (Haiman 2013, Hirsch 2008, Ring 2016, Tavtigian 2009, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs146382972) as "With other allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and five other submitters), and MutDB. The variant was not identified in COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 74 of 276196 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 66 of 23976 chromosomes (freq: 0.003), Other in 1 of 6434 chromosomes (freq: 0.0002), and Latino in 7 of 34316 chromosomes (freq: 0.0002), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala112 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;.;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N;.;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.011	D;D;.;D;.
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.87	.;P;.;P;.
Vest4		0.13, 0.060, 0.18
MVP		0.91
MPC		0.27
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146382972; hg19: chr11-108106399;