rs148191382

chr11-108252902-G-Achr11-108252902-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):c.1888G>A(p.Val630Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,609,322 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. V630A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 2.02

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14175025).
• BP6: Variant 11-108252902-G-A is Benign according to our data. Variant chr11-108252902-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141251.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1888G>A	p.Val630Met	missense_variant	12/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1888G>A	p.Val630Met	missense_variant	12/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250420 Hom.: 1 AF XY: 0.000118 AC XY: 16 AN XY: 135384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000467 AC: 68 AN: 1457234 Hom.: 1 Cov.: 30 AF XY: 0.0000455 AC XY: 33 AN XY: 725220

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000579 AC: 2 AN: 3470

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2023	The p.V630M variant (also known as c.1888G>A), located in coding exon 11 of the ATM gene, results from a G to A substitution at nucleotide position 1888. The valine at codon 630 is replaced by methionine, an amino acid with highly similar properties. This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 2/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2016	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2021	Variant summary: ATM c.1888G>A (p.Val630Met) results in a conservative amino acid change in the encoded protein sequence, that is not located to any known functional domain of the protein. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250420 control chromosomes, predominantly at a frequency of 0.00044 within the Latino subpopulation in the gnomAD database, including 1 homozygote. Though this frequency is somewhat lower than the maximum expected allele frequency for a pathogenic variant in ATM causing Breast Cancer (0.00044 vs 0.001), the occurrence in a homozygous healthy control individual supports a benign role for the variant. c.1888G>A has been reported in the literature in a patient affected with chronic lymphocytic leukemia (CLL), though it was unclear if the variant occurred in germline or somatic state (Jain_2016). The variant was also reported in individuals with personal- and/or family history of breast- and/or ovarian cancer (Tsaousis_2019, Weitzel_2019), however it was also reported in healthy controls (Tiao_2017, Momozawa_2018). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 8/60466 cases, and in 1/53461 controls (Dorling_2021 through LOVD), of note however, the variant in this study was found at a much lower allele frequency in the control cohort than in larger population samples (i.e. gnomAD), therefore no conclusion can be made about association of the variant with disease based on only these data. Co-occurrences with another pathogenic variant has been reported (BARD1 c.1935_1954dup20, p.Glu652ValfsX69; in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2018	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	ATM: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	Observed in individuals with a personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (Jain et al., 2016; Momozawa et al., 2018; Tsaousis et al., 2019; Weitzel et al., 2019; Mizukami et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27468087, 30287823, 31159747, 32980694, 31206626, 33471991, 28652578) -

ATM-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

The ATM c.1888G>A variant is predicted to result in the amino acid substitution p.Val630Met. This variant has been reported in an individual with chronic lymphocytic leukemia (CLL; Table I, Jain et al. 2016. PubMed ID: 27468087), and individual with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626), and an individual undergoing cancer genetic testing (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). It has also been reported in a control individuals from two breast cancer cohort studies (Supp. Data 2, Momozawa et al. 2018. PubMed ID: 30287823; Table S3, Weitzel et al. 2019. PubMed ID: 31206626) and an individual from a CLL cohort study (Table S6, Tiao et al. 2017. PubMed ID: 28652578. This variant is reported in 0.044% of alleles in individuals of Latino descent in gnomAD, including one homozygous observation (http://gnomad.broadinstitute.org/variant/11-108123629-G-A). It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141251/). Although we suspect that this variant may be benign, 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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Val630Met variant was identified in 1 of 972 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Jain 2016). The variant was also identified in dbSNP (ID: rs148191382) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, Integrated Genetics/Laboratory Corporation of America) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 24 of 245222 chromosomes (1 homozygous) at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5462 chromosomes (freq: 0.0002), Latino in 15 of 33478 chromosomes (freq: 0.0004), European in 6 of 111122 chromosomes (freq: 0.00005), East Asian in 1 of 17216 chromosomes (freq: 0.00006), and South Asian in 1 of 30672 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, and Finnish populations. The p.Val630 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 15, 2022

- -

Ataxia-telangiectasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.66	.;P;P
Vest4		0.23, 0.33
MVP		0.95
MPC		0.13
ClinPred		0.044	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs148191382; hg19: chr11-108123629;