ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs148191382
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129681 SCV000184480 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-26 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 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 2022-09-27 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history including 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)
Invitae RCV001079129 SCV000282883 likely benign Ataxia-telangiectasia syndrome 2021-12-09 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
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

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