Submissions for variant NM_000051.4(ATM):c.3628A>G (p.Met1210Val)

gnomAD frequency: 0.00012  dbSNP: rs138212452

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129482	SCV000184252	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	The p.M1210V variant (also known as c.3628A>G), located in coding exon 24 of the ATM gene, results from an A to G substitution at nucleotide position 3628. The methionine at codon 1210 is replaced by valine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole-genome and/or whole-exome sequencing (Zhang J et al. N Engl J Med. 2015 Dec;373:2336-2346). This amino acid position is 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.
GeneDx	RCV000482081	SCV000564629	uncertain significance	not provided	2023-03-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in patients with lung, renal, endometrial, or hematologic cancers (Lu et al., 2015; Zhang et al., 2015; Parry et al., 2017; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 26689913, 28122867, 29684080, 28843361, 26580448, 19781682)
Invitae	RCV000529913	SCV000622437	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000529913	SCV000788484	uncertain significance	Ataxia-telangiectasia syndrome	2017-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129482	SCV000911383	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1210 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 26689913). This variant has been identified in 16/282536 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193060	SCV001361640	uncertain significance	not specified	2019-08-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3628A>G (p.Met1210Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251146 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (4e-05 vs 0.001), allowing no conclusion about variant significance. c.3628A>G has been reported in the literature in individuals affected with lung cancer (Lu_2015, Parry_2017) and core-binding factor acute myeloid leukemia (AML) (Zhang_2015). 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. Five ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000129482	SCV002536517	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
Baylor Genetics	RCV003467109	SCV004210186	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000529913	SCV001458183	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing