rs142358238

Positions:

• chr11-108229312-G-A
• chr11-108229312-G-C
• chr11-108229312-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.320G>A​(p.Cys107Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,612,394 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. 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. C107R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:9
• Conservation: PhyloP100: 3.98

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=0.018790364).
• BP6: Variant 11-108229312-G-A is Benign according to our data. Variant chr11-108229312-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127368.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=7, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000773 (113/1460926) while in subpopulation AFR AF= 0.00242 (81/33456). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4_exome. There are 44 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.320G>A	p.Cys107Tyr	missense_variant	4/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.320G>A	p.Cys107Tyr	missense_variant	4/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000561 AC: 85 AN: 151400 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000962

GnomAD3 exomes AF: 0.000164 AC: 41 AN: 250714 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135560

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1460926 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 726764

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000555 AC: 84 AN: 151468 Hom.: 0 Cov.: 33 AF XY: 0.000528 AC XY: 39 AN XY: 73930

Gnomad4 AFR AF: 0.00189

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000684

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 29, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
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. -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2017	This variant is denoted ATM c.320G>A at the cDNA level, p.Cys107Tyr (C107Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in the compound heterozygous state with a nonsense variant in one individual with Ataxia-telangiectasia (A-T), whose diagnosis was confirmed by clinical observation and radiation sensitivity testing (Bernstein 2003). This variant was also observed in at least two individuals undergoing hereditary cancer testing (Yorczyk 2014, Yurgelun 2015), and in at least one individual with acute myeloid leukemia (Lu 2015). Hirsch et al. (2008) did not identify ATM Cys107Tyr in a series of 31 African-American individuals with breast cancer, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 2/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Cys107Tyr was observed at an allele frequency of 0.21% in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Cys107Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
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	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 23, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: ATM c.320G>A (p.Cys107Tyr) 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. The variant allele was found at a frequency of 0.00017 in 250912 control chromosomes, predominantly at a frequency of 0.0021 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 2-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. c.320G>A has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Bernstein_2003), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), an unaffected control of African American ancestry (Hirsch_2008), a patient undergoing multigene panel testing for cancer (Yorczyk_2015), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), a patient with AML in the TGCA cohort (Lu_2015), a cerebellar ataxia patient (Coutelier_2018), breast cancer cases and controls (Weitzel_2019, Eygelaar_2022, Guindalini_2022) and in PDAC patients (Zimmermann_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in eleven women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over six years of evaluations performed at our laboratory spanning the evidence outlined above, the variant was classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 09, 2022	- -

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.320G>A variant is predicted to result in the amino acid substitution p.Cys107Tyr. This variant has been reported with a nonsense variant in the compound heterozygous state in an individual with ataxia telangiectasia (Bernstein et al. 2003. PubMed ID: 12673797). It has also been observed in an individual with acute myeloid leukemia (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12), and in another individual with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2). However, it has also been observed in four individuals with breast cancer (Eygelaar et al. 2022. PubMed ID: 35039564; Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and found in a control individual from a breast cancer study (Hirsch et al. 2008. PubMed ID: 17333338). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127368/). 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.Cys107Tyr variant was identified in 4 of 36,874 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia tenlangiectasia, acute myeloid leukemia, Lynch Syndrome or breast cancer and was present in 3 of 11,166 control chromosomes (frequency: 0.0003) from healthy individuals (Bernstein 2003, Lu 2015, Yurgelun 2015, Hirsch 2008, Decker 2017). The variant was identified in dbSNP (rs142358238) as “with other allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx, Counsyl and 5 other submitters; and as likely benign by Ambry Genetics and Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 60 of 281,758 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 53 of 24,862 chromosomes (freq: 0.002), Latino in 6 of 35,344 chromosomes (freq: 0.0002), and South Asian in 1 of 30,544 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European or Other populations. This variant was identified in the compound heterozygous state in an individual with ataxia telangiectasia with a co-occurring, pathogenic ATM variant (c.7327C>T, p.Arg2443*; Bernstein 2003). The p.Cys107 residue is conserved in mammals but not in more distantly related organisms, although four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Apr 18, 2024

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.87
Eigen	Benign	-0.018
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;T;T;.;.;.;.;.;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D;N;D;.;N;.;.;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.092	T;T;D;.;T;.;.;.;.;.
Sift4G	Uncertain	0.026	D;D;T;T;D;.;.;.;T;T
Polyphen		0.0020, 0.0050	.;B;.;.;B;B;B;B;B;.
Vest4		0.55, 0.48, 0.81, 0.36
MVP		0.85
MPC		0.28
ClinPred		0.059	T
GERP RS		4.9
Varity_R		0.41
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs142358238; hg19: chr11-108100039;