11-108251060-G-A
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.1595G>A(p.Cys532Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. C532F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: 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 cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1595G>A | p.Cys532Tyr | missense_variant | Exon 10 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000263 AC: 40AN: 152132Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000256 AC: 64AN: 250234 AF XY: 0.000214 show subpopulations
GnomAD4 exome AF: 0.000168 AC: 245AN: 1461780Hom.: 0 Cov.: 35 AF XY: 0.000168 AC XY: 122AN XY: 727186 show subpopulations
Age Distribution
GnomAD4 genome 0.000263 AC: 40AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74446 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:3
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. -
BS1 c.1595G>A, located in exon 10 of the ATM gene, is predicted to result in the substitution of cysteine by tyrosine at codon 532, p.(Cys532Tyr). The variant allele was found in 29/35096 alleles, with a filtered allele frequency of 0.05% at 99% confidence, within the Latino population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). No effect is predicted on splicing by computational tools/SpliceAI and the REVEL meta-predictor score for this variant (0.509) is indeterminate regarding the effect that it may have on protein function. To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been found in breast cancer case-controls studies without significant difference among cancer-affected and healthy controls (PMID: 29659569, 31780696, 17333338, 33471991). This variant has been reported in the ClinVar database (10x likely benign, 8x VUS) and in LOVD (2x likely benign, 5x VUS). Based on currently available information, the variant c.1595G>A should be considered an uncertain significance variant according to ACMG Classification Rules Specified for ATM v1.1. -
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BS1+PP3 -
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not specified Uncertain:1Benign:2Other:1
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1595G>A, in exon 10 that results in an amino acid change, p.Cys532Tyr. This sequence change has been described in the gnomAD database with a frequency of 0.082% in the Latino/Admixed American subpopulation (dbSNP rs35963548). The p.Cys532Tyr change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys532Tyr substitution. This sequence change has been previously described in individuals with different types of cancers, an individual with a history of aplastic anemia or idiopathic pulmonary fibrosis, as well as in healthy individuals (PMID: 29659569, 31780696, 30303537, 28779002, 7913932, 29514593, 30256826, 30995915, FLOSSIES database https://whi.color.com/variant/11-108121787-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Cys532Tyr change remains unknown at this time. -
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Variant summary: ATM c.1595G>A (p.Cys532Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1615282 control chromosomes, predominantly at a frequency of 0.00088 within the Latino subpopulation in the gnomAD database. c.1595G>A has been reported in the literature in individuals affected with various types of cancer (example, breast, mantle cell lymphoma, head and neck squamous cell carcinoma), in settings of multigene panel testing in families negative for BRCA1/2, and in unaffected controls (example, Camacho_2002, Bernstein_2010, Tavtigian_2009, Lu_2015, Tavera-Tapia_2017, Dutil_2019, Girard_2019, Gomes_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 35980532, 20305132, 24728327, 11756177, 34262154, 31780696, 30303537, 33128190, 17333338, 26689913, 26837699, 37436117, 16832357, 27913932, 19781682). ClinVar contains an entry for this variant (Variation ID: 133603). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:2Benign:1
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Observed in individuals with breast, prostate, colorectal, and other cancers, as well as in unaffected controls (PMID: 11756177, 16832357, 17333338, 19781682, 26689913, 27498913, 26837699, 28779002, 27913932, 29522266, 30256826, 29659569, 32325837, 33359728, 35495172, 35534704, 35264596, 34326862, 35980532); 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: 20305132, 28779002, 29659569, 30256826, 16832357, 29522266, 11756177, 19781682, 17333338, 24728327, 27913932, 26689913, 22529920, 24356096, 27498913, 26837699, 30995915, 30303537, 31780696, 32325837, 33436325, 34646395, 34262154, 33128190, 35495172, 33359728, 35534704, 35264596, 34326862, 35980532) -
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Familial cancer of breast Uncertain:1Benign:1
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
ACMG classification criteria: PS4 supporting -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.1595G>A variant is predicted to result in the amino acid substitution p.Cys532Tyr. This variant has been reported in individuals with mantle cell lymphoma, chronic lymphocytic leukemia, prostate cancer, cutaneous melanoma, telomere shortening, or a personal and/or family history of breast and/or ovarian cancer (Camacho et al. 2002. PubMed ID: 11756177; Table S8, Nadeu et al. 2016. PubMed ID: 26837699; Table S1, Tavera-Tapia et al. 2017. PubMed ID: 27913932; Table S3, Girard et al. 2018. PubMed ID: 30303537; Paulo et al. 2018. PubMed ID: 29659569; Arias-Salgado et al. 2019. PubMed ID: 30995915; Dutil et al. 2019. PubMed ID: 31780696; Pastorino et al. 2020. PubMed ID: 32325837; Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, it has also been reported in unaffected control cohorts (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S3, Girard et al. 2018. PubMed ID: 30303537; Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.082% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133603/). 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. -
Hepatoblastoma Uncertain:1
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Breast and/or ovarian cancer Benign:1
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Ataxia-telangiectasia syndrome Benign:1
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Malignant tumor of breast Benign:1
The ATM p.Cys532Tyr variant was identified in 1 of 13394 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and in 5 of 7392 control chromosomes (frequency: 0.001) from healthy individuals (Bernstein_2010_20305132, Bodian_2014_24728327, Hirsch_2008_ 17333338, Renwick_2006_16832357, Tavtigian_2009_19781682). In a study of ATM alterations in mantle cell lymphoma, the variant was identified in the tumours and normal tissue of affected individuals; in addition, healthy blood donors were found to carry the variant at frequencies similar to those of tumor patients, the variant thereby considered a polymorphism found frequently in healthy populations (Camacho 2002 11756177). The variant was also identified in dbSNP (ID: rs35963548) as “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Laboratory Corporation of America; uncertain significance by Invitae, Ambry Genetics, GeneDx, Fulgent Genetics; and classification not provided by ITMI), and Clinvitae (4x), and not in COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 66 of 276820 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24016 chromosomes (freq: 0.00008), Other in 10 of 6456 chromosomes (freq: 0.002), Latino in 27 of 34412 chromosomes (freq: 0.0008), and European Non-Finnish in 27 of 126410 chromosomes (freq: 0.0002), but not in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.2830A>T, p. p.Lys944X), increasing the likelihood the p.Cys532Tyr does not have clinical significance. The p.Cys532 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Hereditary cancer Benign:1
This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -
Hereditary breast ovarian cancer syndrome Benign:1
According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: BS1 (strong benign): gnomAD v4.1.0 Grpmax Filtering AF = 0.001396 (= 0.14%) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at