rs2234996

Variant names:

• chr11-108235599-A-G
• rs2234996
• NM_000051.4:c.332-71A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108235599-A-G
• chr11-108235599-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.332-71A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,330,594 control chromosomes in the GnomAD database, including 1,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (64 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1027 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-108235599-A-G is Benign according to our data. Variant chr11-108235599-A-G is described in ClinVar as Benign. ClinVar VariationId is 1179574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0257 (3920/152360) while in subpopulation SAS AF = 0.0476 (230/4834). AF 95% confidence interval is 0.0425. There are 64 homozygotes in GnomAd4. There are 1835 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.332-71A>G		intron_variant	Intron 4 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.332-71A>G		intron_variant	Intron 4 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3924 AN: 152242 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0477

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0371 AC: 43661 AN: 1178234 Hom.: 1027 AF XY: 0.0372 AC XY: 22030 AN XY: 592146

African (AFR) AF: 0.00667 AC: 175 AN: 26246

American (AMR) AF: 0.0190 AC: 661 AN: 34762

Ashkenazi Jewish (ASJ) AF: 0.0834 AC: 1991 AN: 23880

East Asian (EAS) AF: 0.000142 AC: 5 AN: 35122

South Asian (SAS) AF: 0.0455 AC: 3392 AN: 74474

European-Finnish (FIN) AF: 0.0110 AC: 493 AN: 44706

Middle Eastern (MID) AF: 0.0273 AC: 100 AN: 3658

European-Non Finnish (NFE) AF: 0.0397 AC: 35105 AN: 884990

Other (OTH) AF: 0.0345 AC: 1739 AN: 50396

GnomAD4 genome AF: 0.0257 AC: 3920 AN: 152360 Hom.: 64 Cov.: 32 AF XY: 0.0246 AC XY: 1835 AN XY: 74510

African (AFR) AF: 0.00774 AC: 322 AN: 41594

American (AMR) AF: 0.0212 AC: 324 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0476 AC: 230 AN: 4834

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2574 AN: 68024

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0305 Hom.: 61

Bravo AF: 0.0262

Asia WGS AF: 0.0210 AC: 72 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.82
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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: rs2234996; hg19: chr11-108106326; COSMIC: COSV104591951;