11-108317489-G-C

Variant names:

• chr11-108317489-G-C
• rs587780632
• NM_000051.4:c.6315G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000051.4(ATM):​c.6315G>C​(p.Arg2105Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,610,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2105G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:2
• Conservation: PhyloP100: 3.20
• Publications: 6 publications found

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6315G>C	p.Arg2105Ser	missense_variant	Exon 43 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6315G>C	p.Arg2105Ser	missense_variant	Exon 43 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000599 AC: 9 AN: 150242 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251292 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1460328 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 726522

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.000336 AC: 15 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111060

Other (OTH) AF: 0.0000829 AC: 5 AN: 60284

GnomAD4 genome AF: 0.0000599 AC: 9 AN: 150242 Hom.: 0 Cov.: 28 AF XY: 0.0000683 AC XY: 5 AN XY: 73184

African (AFR) AF: 0.00 AC: 0 AN: 40882

American (AMR) AF: 0.00 AC: 0 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67720

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4

Sep 24, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6315G>C (p.Arg2105Ser) variant has an allele frequency of 0.00011 (0.01%, 26/236,754 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00032 (0.03%, 11/34,260 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 (PMID: 33280026). -

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2105S variant (also known as c.6315G>C), located in coding exon 42 of the ATM gene, results from a G to C substitution at nucleotide position 6315. The arginine at codon 2105 is replaced by serine, an amino acid with dissimilar properties. This variant was identified in a 65-year-old woman with idiopathic retinal telangiectasia (Mauget-Faysse M et al. Invest. Ophthalmol. Vis. Sci. 2003 Aug;44:3257-62). This variant was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33), and was detected in a cohort of 239 high-risk individuals with a family history of pancreatic cancer (Rosner G et al. Clin Transl Gastroenterol, 2024 Feb;15:e00668). In addition, this variant was identified in 5/341 Mexican women who identify as Ashkenazi Jewish (Díaz-Velásquez CE et al. Front Genet, 2023 Feb;14:1094260). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with serine at codon 2105 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with idiopathic ocular telangiectasia (PMID: 12882767), breast cancer (PMID: 25186627), and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has also been identified in 26/251292 chromosomes 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. -

not specified Uncertain:2 Benign:1

Jul 31, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.6315G>C (p.Arg2105Ser) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of 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 0.0001 in 251292 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.0001 vs 0.001), allowing no conclusion about variant significance. c.6315G>C has been reported in the literature in individuals affected with idiopathic retinal telangiectasia (e.g., Mauget-Faysse_2003), breast cancer (e.g., Tung_2015, Feliubadalo_2020), chronic lymphocytic leukemia (Lampson_2023), prostate cancer (Karlsson_2021), and Lynch syndrome-associated cancer and/or polyps (e.g., Yurgelun_2015) as well an individual with a family history of pancreatic cancer (Zhu_2021), however without strong evidence for causality in all cases (e.g., lack of co-segregation and co-occurrence data). The variant was also found in controls (example, Weitzel_2019). These reports therefore 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. The following publications have been ascertained in the context of this evaluation (PMID: 33280026, 12882767, 25186627, 31206626, 25980754, 33436325, 36315919, 33939675). ClinVar contains an entry for this variant (Variation ID: 135767). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nov 23, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6315G>C, in exon 43 that results in an amino acid change, p.Arg2105Ser. This sequence change has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs587780632). The p.Arg2105Ser change has been previously reported in an individual with idiopathic ocular telangiectasia (PMID: 12882767). Additionally, a different sequence change at the same location, p.Arg2105Thr, has been reported in an individual with breast cancer (PMID: 18384426). The p.Arg2105Ser change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2105Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg2105Ser change remains unknown at this time. -

Ataxia-telangiectasia syndrome Uncertain:2 Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with idiopathic ocular telangiectasias as well as in individuals with personal or family history of breast, pancreatic or other cancers (PMID: 12882767, 25186627, 25980754, 33280026, 33436325, 33939675, 35534704, 33471991); This variant is associated with the following publications: (PMID: 25980754, 25186627, 12882767, 33436325, 33280026, 33471991, 33939675, 31206626, 36315919, 35451682, 35534704, 36845387, 23532176) -

ATM-related disorder Uncertain:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.6315G>C variant is predicted to result in the amino acid substitution p.Arg2105Ser. This variant was seen in an individual undergoing Lynch syndrome testing (Yurgelun et al. 2015. PubMed ID: 25980754) and an individual with idiopathic juxtafoveolar retinal telangiectasia (Mauget-Faÿsse et al. 2003. PubMed ID: 12882767). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant was determined to be of uncertain clinical significance by a large consortium evaluating predisposition to prostate cancer (Karlsson et al. 2021. PubMed ID: 33436325), and it has conflicting interpretations in ClinVar, ranging from benign to uncertain clinical significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/135767/). 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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Arg2105Ser variant was identified in 2 of 2580 proband chromosomes (frequency: 0.00078) from individuals or families with Lynch syndrome and ocular telangiectasia and was not identified in 156 control chromosomes from healthy individuals (Mauget-Faysse 2003, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs587780632) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Invitae, Ambry Genetics, GeneDx, and Color Genomics), and Clinvitae (3x as uncertain significance). The variant was not identified in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in control databases in 24 of 246108 chromosomes at a frequency of 0.000098 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 2 of 5480 chromosomes (freq: 0.000365), Latino in 11 of 33580 chromosomes (freq: 0.000328), and Ashkenazi Jewish in 11 of 9842 chromosomes (freq: 0.001118); the variant was not observed in the African, European (Non-Finnish), East Asian, European (Finnish), and South Asian populations. The p.Arg2105Ser residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 Uncertain:1

Mar 27, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		3.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.92		Loss of MoRF binding (P = 0.1672);Loss of MoRF binding (P = 0.1672);
MVP		0.89
MPC		0.28
ClinPred		0.35	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.78
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs587780632; hg19: chr11-108188216; COSMIC: COSV53769689;