ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1073A>G (p.Asn358Ser)

gnomAD frequency: 0.00079  dbSNP: rs149636614
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV002221486 SCV002499281 benign Familial cancer of breast 2022-03-09 reviewed by expert panel curation The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
GeneDx RCV000587788 SCV000149042 uncertain significance not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.1073A>G at the cDNA level, p.Asn358Ser (N358S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn358Ser was reported in an individual with breast cancer, in an individual with a personal history of a Lynch syndrome-related cancer and/or colon polyps, and in an individual undergoing multigene hereditary cancer panel testing (Yurgelun 2015, Mu 2016, Decker 2017). This variant was observed at an allele frequency of 0.23% (55/23,886) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Asn358Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn358Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115133 SCV000186618 likely benign Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Invitae RCV000196425 SCV000254054 benign Ataxia-telangiectasia syndrome 2022-11-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000211956 SCV000593496 uncertain significance not specified 2015-09-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211956 SCV000694170 likely benign not specified 2021-09-27 criteria provided, single submitter clinical testing Variant summary: ATM c.1073A>G (p.Asn358Ser) results in a conservative amino acid change in the encoded protein sequence. 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 0.00016 in 246050 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1073A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Decker_2017) and Lynch Syndrome (e.g. Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=3; benign/likely benign, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga) RCV000587788 SCV000861181 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115133 SCV000910676 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000587788 SCV001143095 likely benign not provided 2019-05-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798306 SCV002043511 uncertain significance Breast and/or ovarian cancer 2019-10-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115133 SCV002529718 likely benign Hereditary cancer-predisposing syndrome 2021-01-28 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355543 SCV001550462 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Asn358Ser variant was identified in 1 of 562 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and triple-negative breast cancer and was present in 2 of 488 control chromosomes (frequency: 0.004) from healthy individuals (Lovejoy 2018, Rosenstein 2006). The variant was also identified in dbSNP (ID: rs149636614) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Integrated Genetics and as uncertain significance by GeneDx, Invitae, University of Chicago and EGL Genetic Diagnostics), LOVD 3.0 (classified as likely benign by VKGL data sharing initiative). The variant was identified in control databases in 60 of 272346 chromosomes at a frequency of 0.0002 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: African in 55 of 23886 chromosomes (freq: 0.002), Other in 1 of 6350 chromosomes (freq: 0.0002), Latino in 3 of 33660 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 125094 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn358 residue is not conserved in mammals and 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 greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000587788 SCV002034052 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000587788 SCV002037982 likely benign not provided no assertion criteria provided clinical testing

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