Submissions for variant NM_000051.4(ATM):c.3242A>G (p.Asn1081Ser)

gnomAD frequency: 0.00003  dbSNP: rs368111672

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130850	SCV000185748	likely benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000588298	SCV000209719	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with ataxia telangiectasia, co-occurring with unspecified biallelic ATM variants, as well as in individuals with breast cancer (Jeddane 2013, Decker 2017); This variant is associated with the following publications: (PMID: 23322442, 24325359, 28873162, 28779002, 30287823)
Invitae	RCV000475427	SCV000546670	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515162	SCV000611358	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731389	SCV000694253	likely benign	not specified	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3242A>G (p.Asn1081Ser) 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 0.00019 in 251266 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3242A>G has been reported in the literature as with clinical significance assessments ranging from Benign/polymorphism to VUS in unaffected controls and affected individuals in settings of multigene panel testing (example, Jeddane_2012, Momozawa_2018, Fujita_2020, Weitzel_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23322442, 24325359, 31206626, 33309985). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000130850	SCV000902741	likely benign	Hereditary cancer-predisposing syndrome	2015-06-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130850	SCV002535846	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149903	SCV003837840	likely benign	Breast and/or ovarian cancer	2022-05-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354773	SCV001549467	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asn1081Ser variant was identified in 4 of 14140 proband chromosomes (frequency: 0.0003) from Moroccan individuals or families with Ataxia-Telangiectasia and Japanese individuals or families with breast cancer, and was present in 2 of 22482 control chromosomes (frequency: 0.00009) from healthy individuals (Jeddane 2013, Momozawa 2018). The variant was also identified in dbSNP (ID: rs368111672) as "With Uncertain significance allele", and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Fulgent Genetics and Integrated Genetics; and likley benign by Color), and LOVD 3.0 (3x as benign). The variant was identified in control databases in 50 of 276988 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 1 of 24026 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European Non-Finnish in 5 of 126520 chromosomes (freq: 0.00004), and South Asian in 41 of 30780 chromosomes (freq: 0.001) while not observed in the Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn1081 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that the variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.