ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.295A>G (p.Ser99Gly) (rs137882485)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588846 SCV000149078 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.295A>G at the cDNA level, p.Ser99Gly (S99G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has been observed in at least one individual with breast cancer (Tavtigian 2009), at least one individual with B-cell chronic lymphocytic leukemia (L?hdesm?ki 2004), and at least one individual with advanced cancer, not otherwise specified (Mandelker 2017). ATM Ser99Gly was observed at an allele frequency of 0.38% (39/10,144) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). ATM Ser99Gly is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ser99Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115169 SCV000183799 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000196996 SCV000254077 benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515313 SCV000611354 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855626 SCV000694242 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: ATM c.295A>G (p.Ser99Gly) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 250934 control chromosomes, predominantly at a frequency of 0.0038 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4 fold of 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 Ashkenazi Jewish origin. c.295A>G has been reported in the literature in individuals affected with Breast Cancer and CLL but was also found in controls (Lahdesmaki_2004, Tavtigian_2009, Tung_2015, Tiao_2017, Girard_2019, Mandelker_2017). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3481_3491delGAAGATACTAG, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 (6x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000196996 SCV000790963 uncertain significance Ataxia-telangiectasia syndrome 2017-04-17 criteria provided, single submitter clinical testing
Mendelics RCV000196996 SCV000838467 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115169 SCV000902647 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000196996 SCV001260303 uncertain significance Ataxia-telangiectasia syndrome 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
True Health Diagnostics RCV000115169 SCV000787857 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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