11-108271144-A-G

Variant names:

• chr11-108271144-A-G
• rs587779829
• NM_000051.4:c.2919A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000051.4(ATM):​c.2919A>G​(p.Leu973Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L973L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.001733
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 0.185
• Publications: 2 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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-108271144-A-G is Benign according to our data. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361. Variant chr11-108271144-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127361.
• BP7: Synonymous conserved (PhyloP=0.185 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2919A>G	p.Leu973Leu	splice_region_variant, synonymous_variant	Exon 19 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2919A>G	p.Leu973Leu	splice_region_variant, synonymous_variant	Exon 19 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251358 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727184

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111886

Other (OTH) AF: 0.0000497 AC: 3 AN: 60384

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74274

African (AFR) AF: 0.0000483 AC: 2 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Jun 14, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with personal and/or family history of breast cancer, but also in healthy controls (Decker 2017, Kraus 2017, Tiao 2017); This variant is associated with the following publications: (PMID: 27616075, 28779002, 28652578, 27535533) -

Jul 31, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may interfere with normal RNA splicing. -

May 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.2919A>G; p.Leu973= variant (rs587779829) is reported in an individual with a personal and family history of breast cancer (Kraus 2017), but the variant was not determined to be causative. This variant is also reported in ClinVar (Variation ID: 127361). It is observed in the general population with an overall allele frequency of 0.004% (12/282730 alleles) in the Genome Aggregation Database (v2.1.1). This is a synonymous variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102. PMID: 27616075. -

Ataxia-telangiectasia syndrome Benign:2

Apr 06, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Uncertain:1

Mar 11, 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.2919A>G (p.Leu973Leu) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 251358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although reported as a VUS in settings of multigene panel testing for Inherited cancers (example, Kraus_2016, Okawa_2023), to our knowledge, no occurrence of c.2919A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27616075, 36243179). ClinVar contains an entry for this variant (Variation ID: 127361). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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.Leu973= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in the following databases: dbSNP (ID: rs587779829) as With “Uncertain significance allele”, ClinVar (reported 3x, as likely benign by Ambry Genetics, Invitae and uncertain significance by GeneDx), Clinvitae (reported 3x). The variant was identified in control databases in 11 of 277110 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24014 chromosomes (freq: 0.00008), European Non-Finnish in 7 of 126668 chromosomes (freq: 0.000055), and South Asian in 2 of 30778 chromosomes (freq: 0.000065). while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. This variant was identified by our laboratory with a co-occurring pathogenic BRCA2 variant (c.5350_5351delAA, p.Asn1784Hisfsx2), increasing the likelihood that the p.Leu973= variant does not have clinical significance. The p.Leu973= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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. -

ATM-related disorder Benign:1

Dec 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Familial cancer of breast Benign:1

May 10, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		0.18
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.10
Splicevardb		1.0
SpliceAI score (max)		0.090		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: rs587779829; hg19: chr11-108141871;