rs587779829

Positions:

• chr11-108271144-A-G
• chr11-108271144-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000051.4(ATM):​c.2919A>G​(p.Leu973=) 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:3 B:6
• Conservation: PhyloP100: 0.185

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 Likely_benign. Variant got -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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127361.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.185 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2919A>G	p.Leu973=	splice_region_variant, synonymous_variant	19/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2919A>G	p.Leu973=	splice_region_variant, synonymous_variant	19/63		NM_000051.4	P1

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

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251358 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135878

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.0000567

Gnomad4 OTH exome AF: 0.0000497

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

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 06, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 15, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 11, 2024

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2021

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) -

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.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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2019

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

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 10, 2024

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

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.10
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

Publications

LitVar

Other links and lift over

dbSNP: rs587779829; hg19: chr11-108141871; COSMIC: COSV105845350;