11-108304660-G-C

Variant names:

• chr11-108304660-G-C
• rs3092828
• NM_000051.4:c.5497-15G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.5497-15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,611,928 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (35 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: -0.798
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-108304660-G-C is Benign according to our data. Variant chr11-108304660-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136446.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00378 (575/152196) while in subpopulation SAS AF = 0.00622 (30/4826). AF 95% confidence interval is 0.00498. There are 5 homozygotes in GnomAd4. There are 280 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5497-15G>C		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.5497-15G>C		intron	N/A	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5497-15G>C		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.5497-15G>C		intron	N/A	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*561-15G>C		intron	N/A	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152080 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00431 AC: 1080 AN: 250546 AF XY: 0.00446

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00519 AC: 7577 AN: 1459732 Hom.: 35 Cov.: 31 AF XY: 0.00527 AC XY: 3827 AN XY: 726308

African (AFR) AF: 0.000777 AC: 26 AN: 33442

American (AMR) AF: 0.00166 AC: 74 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00391 AC: 102 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.00669 AC: 577 AN: 86184

European-Finnish (FIN) AF: 0.0114 AC: 608 AN: 53278

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.00533 AC: 5920 AN: 1110286

Other (OTH) AF: 0.00423 AC: 255 AN: 60332

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152196 Hom.: 5 Cov.: 32 AF XY: 0.00376 AC XY: 280 AN XY: 74412

African (AFR) AF: 0.000722 AC: 30 AN: 41536

American (AMR) AF: 0.00138 AC: 21 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00513 Hom.: 1

Bravo AF: 0.00293

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	1	1	Ataxia-telangiectasia syndrome (2)
-	-	2	Familial cancer of breast (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.25
DANN	Benign	0.66
PhyloP100		-0.80
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: rs3092828; hg19: chr11-108175387; COSMIC: COSV104592101;