Submissions for variant NM_000051.4(ATM):c.931A>G (p.Ile311Val)

gnomAD frequency: 0.00001  dbSNP: rs876658322

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216322	SCV000273387	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The p.I311V variant (also known as c.931A>G), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 931. The isoleucine at codon 311 is replaced by valine, an amino acid with highly similar properties. This variant was detected in a Spanish family with hereditary breast and ovarian cancer (HBOC) (Tavera-Tapia A et al. Breast Cancer Res Treat, 2017 02;161:597-604). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471282	SCV000547030	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 311 of the ATM protein (p.Ile311Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with ATM-related cancer (PMID: 27913932). ClinVar contains an entry for this variant (Variation ID: 229990). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586464	SCV000694392	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.931A>G (p.Ile311Val) variant located in the Armadillo-type fold domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in the large, broad control population, ExAC, 0/120068 control chromosomes. A publication cites the variant in an HBOC individual with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color Diagnostics, LLC DBA Color Health	RCV000216322	SCV000903400	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 311 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250896 chromosomes 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.
GeneDx	RCV000586464	SCV001792928	uncertain significance	not provided	2023-07-03	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; Observed in individuals with breast and/or ovarian cancer (Tavera-Tapia et al., 2017); This variant is associated with the following publications: (PMID: 33471991, 27913932)
Sema4, Sema4	RCV000216322	SCV002530758	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	curation
Baylor Genetics	RCV004567507	SCV005055849	uncertain significance	Familial cancer of breast	2024-03-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000471282	SCV002089593	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-15	no assertion criteria provided	clinical testing