Submissions for variant NM_000051.4(ATM):c.1436A>G (p.Asp479Gly)

gnomAD frequency: 0.00001  dbSNP: rs1555070958

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567124	SCV000665379	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The p.D479G variant (also known as c.1436A>G), located in coding exon 9 of the ATM gene, results from an A to G substitution at nucleotide position 1436. The aspartic acid at codon 479 is replaced by glycine, an amino acid with similar properties. This variant was reported in 1/270 Austrian Hereditary Breast and/or Ovarian Cancer families, who had prior negative BRCA1/2 genetic testing (Thorstenson YR et al. Cancer Res. 2003 Jun;63:3325-33).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590526	SCV000694183	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1436A>G (p.Asp479Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 121338 control chromosomes and has been reported in one patient with breast cancer, without strong evidence for causality. Due to lack of clinical and functional evidence, this variant is classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627958	SCV000748844	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 479 of the ATM protein (p.Asp479Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12810666). ClinVar contains an entry for this variant (Variation ID: 481165). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000567124	SCV001339873	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 479 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with hereditary breast and ovarian cancer (PMID: 12810666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197304	SCV001367967	uncertain significance	Familial cancer of breast	2019-05-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP1.
Baylor Genetics	RCV001197304	SCV005057144	uncertain significance	Familial cancer of breast	2023-12-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000590526	SCV005371757	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports a deleterious effect on splicing; Observed in an individual with breast and/or ovarian cancer (PMID: 12810666); This variant is associated with the following publications: (PMID: 12810666)