Submissions for variant NM_000051.4(ATM):c.1888G>A (p.Val630Met)

gnomAD frequency: 0.00004  dbSNP: rs148191382

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129681	SCV000184480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.V630M variant (also known as c.1888G>A), located in coding exon 11 of the ATM gene, results from a G to A substitution at nucleotide position 1888. The valine at codon 630 is replaced by methionine, an amino acid with highly similar properties. This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 2/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
GeneDx	RCV000590311	SCV000278812	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (Jain et al., 2016; Momozawa et al., 2018; Tsaousis et al., 2019; Weitzel et al., 2019; Mizukami et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27468087, 30287823, 31159747, 32980694, 31206626, 33471991, 28652578)
Invitae	RCV001079129	SCV000282883	likely benign	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731482	SCV000694203	likely benign	not specified	2021-09-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1888G>A (p.Val630Met) results in a conservative amino acid change in the encoded protein sequence, that is not located to any known functional domain of the protein. 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 0.0001 in 250420 control chromosomes, predominantly at a frequency of 0.00044 within the Latino subpopulation in the gnomAD database, including 1 homozygote. Though this frequency is somewhat lower than the maximum expected allele frequency for a pathogenic variant in ATM causing Breast Cancer (0.00044 vs 0.001), the occurrence in a homozygous healthy control individual supports a benign role for the variant. c.1888G>A has been reported in the literature in a patient affected with chronic lymphocytic leukemia (CLL), though it was unclear if the variant occurred in germline or somatic state (Jain_2016). The variant was also reported in individuals with personal- and/or family history of breast- and/or ovarian cancer (Tsaousis_2019, Weitzel_2019), however it was also reported in healthy controls (Tiao_2017, Momozawa_2018). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 8/60466 cases, and in 1/53461 controls (Dorling_2021 through LOVD), of note however, the variant in this study was found at a much lower allele frequency in the control cohort than in larger population samples (i.e. gnomAD), therefore no conclusion can be made about association of the variant with disease based on only these data. Co-occurrences with another pathogenic variant has been reported (BARD1 c.1935_1954dup20, p.Glu652ValfsX69; in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000129681	SCV000821832	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129681	SCV000903507	likely benign	Hereditary cancer-predisposing syndrome	2016-10-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001731482	SCV002065710	uncertain significance	not specified	2018-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129681	SCV002533486	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-15	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590311	SCV002544605	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	ATM: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149894	SCV003837828	likely benign	Breast and/or ovarian cancer	2022-06-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001731482	SCV004027166	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398759	SCV004103296	uncertain significance	ATM-related condition	2023-03-28	criteria provided, single submitter	clinical testing	The ATM c.1888G>A variant is predicted to result in the amino acid substitution p.Val630Met. This variant has been reported in an individual with chronic lymphocytic leukemia (CLL; Table I, Jain et al. 2016. PubMed ID: 27468087), and individual with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626), and an individual undergoing cancer genetic testing (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). It has also been reported in a control individuals from two breast cancer cohort studies (Supp. Data 2, Momozawa et al. 2018. PubMed ID: 30287823; Table S3, Weitzel et al. 2019. PubMed ID: 31206626) and an individual from a CLL cohort study (Table S6, Tiao et al. 2017. PubMed ID: 28652578. This variant is reported in 0.044% of alleles in individuals of Latino descent in gnomAD, including one homozygous observation (http://gnomad.broadinstitute.org/variant/11-108123629-G-A). It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141251/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356176	SCV001551267	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Val630Met variant was identified in 1 of 972 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Jain 2016). The variant was also identified in dbSNP (ID: rs148191382) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, Integrated Genetics/Laboratory Corporation of America) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 24 of 245222 chromosomes (1 homozygous) at a frequency of 0.0001 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: Other in 1 of 5462 chromosomes (freq: 0.0002), Latino in 15 of 33478 chromosomes (freq: 0.0004), European in 6 of 111122 chromosomes (freq: 0.00005), East Asian in 1 of 17216 chromosomes (freq: 0.00006), and South Asian in 1 of 30672 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, and Finnish populations. The p.Val630 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129681	SCV001950159	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing