11-108329202-T-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_ModeratePM3PP3PP1PS4
This summary comes from the ClinGen Evidence Repository: The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI ≥1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID:18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115930/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.7271T>G | p.Val2424Gly | missense_variant | Exon 49 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250994Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135682
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461626Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727116
GnomAD4 genome 0.0000591 AC: 9AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:9Other:1
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Variant interpretted as pathogenic and reported on 11/30/2017 by GTR ID Trillium Health Partners. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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The ATM c.7271T>G; p.Val2424Gly variant (rs28904921) is associated with an increased risk for breast and other cancers (Goldgar 2011, Kurian 2014, Stankovic 1998, Tavtigian 2009, Yurgelun 2015). It is also reported in association with autosomal recessive ataxia telangiectasia in both a homozygous state and in a compound heterozygous state with other ATM variants. (McConville 1996, Stankovic 1998). The p.Val2424Gly variant does not alter the abundance of the ATM protein but several studies have shown that it impairs ATM kinase activity and DNA repair (Barone 2009, Mitui 2009, Stankovic 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3023). It is found in the general population with an overall allele frequency of 0.004% (12/282354 alleles) in the Genome Aggregation Database. The valine at codon 2424 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-1230. Goldgar DE et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-2009. McConville CM et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet. 1996 Aug;59(2):320-30 Mitui M et al. Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat. 2009 Jan;30(1):12-21 Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-345. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-446. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. -
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The ATM p.Val2424Gly variant was identified in 20 of 14588 proband chromosomes (frequency: 0.0013) from individuals or families with contralateral and bilateral breast cancers (Bernstein 2003, Bernstein 2010, Chenevix-Trench 2002, Goldgar 2011, Waddell 2006). The variant was also identified in dbSNP (ID: rs28904921) as “with pathogenic allele”, in the ClinVar database (as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 additional clinical laboratories, and as likely pathogenic by Counsyl), in the Cosmic database (2x as pathogenic), and in the LOVD 3.0 database (6x as pathogenic). The variant was not identified in the COGR or in the MutDB databases. The variant was also identified in control databases including the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles and in 14 of 276788 chromosomes at a frequency of 0.00005 in the Genome Aggregation Database (Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34412 chromosomes (freq: 0.00003), and European Non-Finnish in 13 of 126414 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vivo analyses of cell lines established from individuals heterozygous for the c.7271T>G variant suggest that this ATM variant acts in a dominant negative manner so that the wild-type enzyme is unable to function normally in the presence of the mutant protein. Results reveal that the mutant ATM protein from the c.7271T>G heterozygotes is stable but intrinsically defective as a kinase. It appears that, in cells with these mutant ATM alleles, p53 phosphorylation and stabilization are reduced, which presumably decreases the effectiveness of the cell cycle checkpoint (Chenevix-Trench 2002). In another study, the c.7271T>G variant was genotyped and modified segregation analysis was used to estimate the breast cancer penetrance. Women carrying the variant, ATM c.7271T>G demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2. Separate analyses of the 15 families carrying the ATM c.7271T>G variant found that this variant increased breast cancer risk by a factor of 8.0 compared with 4.4 for families with other ATM variants (Goldgar 2011). Another study confirmed that the p.Val2424Gly variant confers a moderate risk of breast cancer, with an estimated hazard ratio of 6.1. Furthermore, the study revealed that the V2424 allele was found across seven vertebrate sequences. To elucidate the molecular effects of the ATM 7271T>G variant, a study carried out expression profiling and demonstrated that the ATM 7271T>G variant acts largely as a dominant negative causing differences in expression profiles of many genes (Waddell 2006). The p.Val2424 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
PS3, PS4, PM2, PM3, PP1, PP3, PP5 -
Case-control studies suggest this variant is associated with breast cancer and confers a higher risk than other ATM variants (Stankovic 1998, Chenevix-Trench 2002, Bernstein 2006, Goldgar 2011, van Os 2016, Southey 2016, Thompson 2016, Decker 2017); Published functional studies demonstrate a damaging effect: cells heterozygous for this variant demonstrate radiosensitivity and decreased kinase activity (Stewart 2001, Chenevix-Trench 2002, Barone 2009, Mitui 2009, Taylor 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Huang 2015, Hart 2016, Southey 2016, Thompson 2016, Decker 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 26506520, 27595995, 28580595, 27913932, 28452373, 25186627, 29915382, 30549301, 8755918, 16958054, 21787400, 17001622, 24733792, 15928302, 9463314, 24763289, 18634022, 9288106, 22529920, 19781682, 24088041, 11382771, 26786923, 19431188, 26662178, 11830610, 26633545, 26985847, 25980754, 27273131, 14871810, 27528516, 26681312, 28779002, 28454591, 27988859, 28643015, 28840378, 28691344, 29034753, 27798748, 28821472, 28390840, 28439798, 29719442, 29271107, 29665859, 29661970, 29422015, 29341116, 29555025, 27084275, 29506079, 25040471, 18575927, 30197789, 27978560, 31447099) -
The frequency of this variant in the general population, 0.000085 (11/128854 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals/families with breast cancer (PMIDs: 32427313 (2020), 27798748 (2017), 25186627 (2015), 24733792 (2014), 16958054 (2006), 16832357 (2006), 17001622 (2006), 14562025 (2003)) as well as individuals with other cancers such as gastric, prostate, or leukemia (PMIDs: 32338768 (2020), 26506520 (2015), 9892178 (1999), 9288106 (1997)). This variant was shown to be strongly associated with breast cancer risk among Caucasian women (PMIDs: 27595995 (2016), 21787400 (2011)), with estimated cumulative breast cancer risk to age 70 years (penetrance) 34-60% (PMIDs: 17001622 (2006), 16958054 (2006), 11830610 (2002)). In addition, this variant has been reported in individuals/families with ataxia-telangiectasia (PMIDs: 30549301 (2019), 18575927 (2008), 9463314 (1998), 8755918 (1996)). Furthermore, experimental studies have demonstrated that this variant results in reduced/null ATM kinase activity (PMID: 18634022 (2009), 11830610 (2002), 11382771 (2001)). Based on the available information, this variant is classified as pathogenic. -
Ataxia-telangiectasia syndrome Pathogenic:8
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (AT; MIM#208900) and cancer susceptibility (MIM#114480). (I) 0106 - This gene is associated with autosomal recessive ataxia-telangiectasia. However, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastic, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMID: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated FAT domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals in a homozygous or compound heterozygous state with ataxia-telangiectasia, with a predominantly mild form of disease (ClinVar, PMID: 9463314, 30549301). This variant has also been reported to cause a significantly increased risk of breast cancer in heterozygous females (ClinVar, PMID: 27595995). Lifetime risk of breast cancer in women heterozygous for this variant is 52-69% (PMID: 16958054, 26662178). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on patient cells and transfected human cell lines show that this variant results in protein expression similar to wild-type, but significantly reduced kinase activity (PMID: 11382771, 18634022). This variant may act in a dominant negative manner (PMID: 11830610, 17001622). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant has been previously reported as disease-causing and was found twice in our laboratory in affected individuals who carried second pathogenic variants in the gene. -
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2424 of the ATM protein (p.Val2424Gly). This variant is present in population databases (rs28904921, gnomAD 0.01%). This missense change has been observed in individual(s) with gastric cancer, breast cancer, autosomal recessive ataxia-telangiectasia (PMID: 8755918, 9463314, 11830610, 16958054, 18575927, 19781682, 21787400, 24733792, 26506520). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3023). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 11382771, 11830610, 18634022, 19431188). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
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Familial cancer of breast Pathogenic:5
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This c.7271T>G (p.Val2424Gly) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8755918, 9463314, 18575927]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 18634022]. This variant has seen observed at the heterozygous state in at least 24 patients from two cohorts of breast cancer patients [PMID 19781682, 21787400]. Statistical analysis in one cohort estimated the risk factor for breast cancer to be 8.0 for carriers of this variant compared to 4.4 for families carriers of other pathogenic variants. This variant was observed in 3 Europeans (Non Finnish) at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/11-108199929-T-G). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Val2424Gly change to be deleterious. It is thus interpreted as a pathogenic variant. -
PP3, PS3_Moderate, PS4, PM3_Very strong, PP1 -
The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI greater than or equal to 1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
This missense variant replaces valine with glycine at codon 2424 in the FAT domain of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in significantly decreased ATM kinase activity (PMID: 11382771, 11830610, 18634022). This variant has been reported in over 50 individuals affected with breast cancer (PMID: 9463314, 11830610, 16958054, 21787400, 24733792, 25186627, 26681312, 27595995, 27798748, 28779002). Several large breast cancer case-control studies reported this variant to confer increased risk of the disease (PMID: 27595995, 33471991, 33509806), comparable to BRCA1 and BRCA2 pathogenic mutations (PMID: 11830610, 16958054, 26662178). This variant has been observed in multiple families affected with attenuated ataxia-telangiectasia in homozygous state or compound heterozygous state with pathogenic truncation variants (PMID: 8755918, 9463314, 18575927, 27528516, 30549301, 32748564). This variant has been identified in 12/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The p.V2424G pathogenic mutation (also known as c.7271T>G), located in coding exon 48 of the ATM gene, results from a T to G substitution at nucleotide position 7271. The valine at codon 2424 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with ataxia-telangiectasia (AT) (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Marelli C et al. Hum. Mutat. 2016 Dec;37:1340-1353), colorectal cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471) as well as individuals with personal history of breast cancer (Kurian AW et al. J. Clin. Oncol. 2014 Jul;32:2001-9; Tung N et al. Cancer. 2015 Jan;121:25-33; Southey MC et al. J. Med. Genet. 2016 12;53:800-811; Susswein LR et al. Genet. Med. 2016 08;18:823-32; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This alteration impacts an evolutionarily conserved residue in the 3' FAT functional domain of the ATM protein and has been shown to act in a dominant-negative manner (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Waddell N et al. Genes Chromosomes Cancer. 2006 Dec;45:1169-81). In a large case-control study the p.V2424G pathogenic mutation was shown to be associated with a significantly increased risk for breast cancer (OR=11.0, 95% CI 1.42 to 85.7) (Southey MC et al. J. Med. Genet. 2016 12;53:800-811). Pedigree analyses of numerous p.V2424G-carrier families with multiple cases of breast cancer have produced lifetime cumulative breast cancer risk estimates ranging from 52% to 69% for this specific allele (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Chenevix-Trench G et al. J. Natl. Cancer Inst. 2002 Feb;94:205-15; Bernstein JL et al. Hum. Mutat. 2006 Nov;27:1122-8; Goldgar D et al. Breast Cancer Res. 2011 Jul;13:R73). Functional assays show that this mutation retains some residual kinase activity and has been seen in some patients with a milder AT phenotype (Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -
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Breast and/or ovarian cancer Pathogenic:1
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Inherited breast cancer and ovarian cancer Pathogenic:1
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Ataxia - telangiectasia variant Pathogenic:1
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NICE approved PARP inhibitor treatment Pathogenic:1
PS3_Moderate,PS4,PM3_Strong,PP3 -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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T-cell prolymphocytic leukemia Pathogenic:1
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Breast neoplasm Pathogenic:1
Found in a male patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with bilateral breast cancer diagnosed at age 88 and 93. -
ATM-related disorder Pathogenic:1
The ATM c.7271T>G variant is predicted to result in the amino acid substitution p.Val2424Gly. This variant has been reported in individuals with ataxia telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314; McConville et al. 1996. PubMed ID: 8755918), multiple individuals with breast cancer (see for example - Bernstein et al. 2006. PubMed ID: 16958054; Goldgar et al. 2011. PubMed ID: 21787400), and one individual with gastric cancer (Huang et al. 2015. PubMed ID: 26506520). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3023/). This variant is interpreted as pathogenic. -
Breast cancer, susceptibility to Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at