Submissions for variant NM_000051.4(ATM):c.6343G>A (p.Val2115Ile)

gnomAD frequency: 0.00011  dbSNP: rs587780634

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122874	SCV000166132	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2115 of the ATM protein (p.Val2115Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with chronic lymphocytic leukemia (CLL) and breast cancer (PMID: 28652578, 31871109, 35264596). ClinVar contains an entry for this variant (Variation ID: 135770). 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. 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.
Ambry Genetics	RCV000131631	SCV000186654	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	The p.V2115I variant (also known as c.6343G>A), located in coding exon 42 of the ATM gene, results from a G to A substitution at nucleotide position 6343. The valine at codon 2115 is replaced by isoleucine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131631	SCV000292178	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2115 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. In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and 1/53461 controls (OR=5.305, 95%CI 0.639 to 44.07, p-value=0.13; PMID: 33471991). This variant has been observed in individuals affected with ovarian cancer (PMID: 26689913), chronic lymphocytic leukemia (PMID: 28652578) and thyroid cancer (PMID: 29684080). This variant has been identified in 8/244556 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	RCV000237090	SCV000292473	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21787400, 26689913, 28652578, 29684080, 31871109, 33471991, 23532176, 35264596)
Mendelics	RCV000122874	SCV000838570	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122874	SCV001264708	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269134	SCV001448389	uncertain significance	not specified	2020-11-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6343G>A (p.Val2115Ile) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 3.2e-05 in 249350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6343G>A has been reported in the literature in individuals affected with CLL (example, Tiao_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000237090	SCV001713582	uncertain significance	not provided	2019-08-26	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000122874	SCV002012385	uncertain significance	Ataxia-telangiectasia syndrome	2021-09-09	criteria provided, single submitter	clinical testing	The ATM c.6343G>A (p.Val2115Ile) missense change has a maximum frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108188244-G-A). This variant is reported 3x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/variant/11-108188244-G-A). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798397	SCV002042742	uncertain significance	Breast and/or ovarian cancer	2022-04-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131631	SCV002537266	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288612	SCV002581333	uncertain significance	Familial cancer of breast	2022-02-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483232	SCV002779441	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001269134	SCV004024705	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000122874	SCV002083462	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-01	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483488	SCV004228509	not provided	Ataxia-telangiectasia syndrome; Hereditary cancer-predisposing syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-20-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.